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Sagar K, Akhtar S, Kumar N, Tomar AK, Roy A, Hote MP, Arava S, Yadav S, Sharma A. CCR5-Mediated Reprogramming of Regulatory T Cells and Monocytic-Myeloid-Derived Suppressor Cells in Young Dyslipidemic Individuals: A Plausible Therapeutic Approach. Immunology 2025. [PMID: 40387394 DOI: 10.1111/imm.13941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 02/27/2025] [Accepted: 04/21/2025] [Indexed: 05/20/2025] Open
Abstract
Chemokine receptor CCR5 is upregulated in the regulatory T cells (Tregs) and monocytic-myeloid-derived suppressor cells (M-MDSCs) of young dyslipidemic individuals. In this study, we investigated the role of CCR5 in regulating the phenotypic and functional plasticity of Tregs and M-MDSCs during the preclinical phase of atherosclerosis. Inflammatory conditions induce a phenotypic shift in Tregs and M-MDSCs, characterised by enhanced expression of CCR5 and pro-inflammatory cytokines. Tregs from dyslipidemic (DLP) and coronary artery disease (CAD) patients exhibited a mixed Th1/Th17/Treg phenotype, whilst M-MDSCs displayed elevated markers of activation and inflammation. CCR5 inhibition via DAPTA (10-8 M) restored the immune suppressive phenotype and function of Tregs and M-MDSCs in vitro. Migration of dysfunctional Tregs and M-MDSCs to CCL5 stimulus was also reduced after DAPTA treatment in vitro. In vivo, DAPTA reduced IL-12 expression and elevated IL-10 expression in Tregs and M-MDSCs. Therapeutically targeting CCR5 in Tregs and M-MDSCs of young naive dyslipidemic individuals aids in the dampening of early inflammation and can prevent the progression of atherosclerosis.
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Affiliation(s)
- Komal Sagar
- Department of Biochemistry, All India Institute of Medical Sciences, AIIMS, New Delhi, India
| | - Shamima Akhtar
- Department of Biochemistry, All India Institute of Medical Sciences, AIIMS, New Delhi, India
| | - Nikita Kumar
- Department of Biochemistry, All India Institute of Medical Sciences, AIIMS, New Delhi, India
| | | | - Ambuj Roy
- Department of Cardiology, AIIMS, New Delhi, India
| | - Milind P Hote
- Department of Cardiothoracic and Vascular Surgery, AIIMS, New Delhi, India
| | | | - Savita Yadav
- Department of Biophysics, AIIMS, New Delhi, India
| | - Alpana Sharma
- Department of Biochemistry, All India Institute of Medical Sciences, AIIMS, New Delhi, India
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Yan D, Zhan S, Guo C, Han J, Zhan L, Zhou Q, Bing D, Wang X. The role of myocardial regeneration, cardiomyocyte apoptosis in acute myocardial infarction: A review of current research trends and challenges. J Cardiol 2025; 85:283-292. [PMID: 39393490 DOI: 10.1016/j.jjcc.2024.09.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 09/30/2024] [Accepted: 09/30/2024] [Indexed: 10/13/2024]
Abstract
PURPOSE This paper aims to review the research progress in repairing injury caused by acute myocardial infarction, focusing on myocardial regeneration, cardiomyocyte apoptosis, and fibrosis. The goal is to investigate the current research trends and challenges in the field of myocardial injury repair. METHODS The review delves into the latest research on myocardial regeneration, cardiomyocyte apoptosis, and fibrosis following acute myocardial infarction. It highlights stem cell transplantation and gene therapy as key areas of current research focus, while emphasizing the significance of cardiomyocyte apoptosis and fibrosis in the myocardial injury repair process. Additionally, the review addresses the challenges and unresolved issues that require further investigation in the field of myocardial injury repair. SUMMARY Acute myocardial infarction is a prevalent cardiovascular condition that results in myocardial damage necessitating repair. Myocardial regeneration plays a crucial role in repairing myocardial injury, with current research focusing on stem cell transplantation and gene therapy. Cardiomyocyte apoptosis and fibrosis are key factors in the repair process, significantly impacting the restoration of myocardial structure and function. Nonetheless, there remain numerous challenges and unresolved issues that warrant further investigation in the realm of myocardial injury repair.
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Affiliation(s)
- Dan Yan
- Institute of Cardiovascular Diseases, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan, China; Wuhan Asia Heart Hospital, Wuhan University of Science and Technology, Wuhan, Hubei, China; Institute of Pharmaceutical Innovation, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei, China.
| | - Shifang Zhan
- Institute of Cardiovascular Diseases, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan, China
| | - Chenyu Guo
- Institute of Cardiovascular Diseases, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan, China
| | - Jiawen Han
- Institute of Cardiovascular Diseases, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan, China
| | - Lin Zhan
- Institute of Cardiovascular Diseases, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan, China
| | - Qianyi Zhou
- Institute of Cardiovascular Diseases, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan, China
| | - Dan Bing
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Xiaoyan Wang
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Key Laboratory of Emergency and Trauma, Ministry of Education, College of Emergency and Trauma, Hainan Medical University, Haikou, China.
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Sharma G, Vela RJ, Powell L, Deja S, Fu X, Burgess SC, Malloy CR, Jessen ME, Peltz M. Metabolic and transcriptomic insights into temperature controlled hypothermic preservation of human donor hearts. J Heart Lung Transplant 2025:S1053-2498(25)01836-4. [PMID: 40081628 DOI: 10.1016/j.healun.2025.03.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 02/28/2025] [Accepted: 03/05/2025] [Indexed: 03/16/2025] Open
Abstract
BACKGROUND Heart transplantation (HT) is the gold standard for end-stage heart disease. Donor heart preservation is an important factor that influences post-transplant success. Recently, temperature-controlled storage has demonstrated reduced primary graft dysfunction compared to standard cold storage though mechanisms are poorly understood. We hypothesized that alterations in gene expression and metabolomics offer insight into improved outcomes observed with temperature-controlled storage. METHODS We conducted a comprehensive study to investigate the metabolic and transcriptomic responses of donor hearts preserved for 6 hours using a temperature-controlled hypothermic preservation (TCHP) system compared to conventional static cold storage (SCS). Metabolic assessments were carried out using high-resolution 1H and 31P nuclear magnetic resonance (NMR), and liquid chromatography/mass spectrometry (LC-MS) analysis on tissues obtained from various cardiac regions. Lactate, alanine, adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), nicotinamide adenine dinucleotide (NAD), reduced nicotinamide adenine dinucleotide (NADH), phosphocreatine, and inorganic phosphate were measured, and metabolite ratios were calculated. Transcriptomic profiling was conducted using high throughput RNA sequencing followed by bioinformatic analysis to explore gene expression changes associated with different preservation methods. RESULTS Metabolic analyses revealed largely similar profiles between hearts preserved with TCHP and SCS. Energy metabolite ratios were comparable between preservation methods. Transcriptomic analysis unveiled a high correlation between preservation methods but also showed differential gene expression in energy metabolism and inflammation/immune-related pathways. CONCLUSIONS Our study demonstrates that TCHP maintains similar high-energy phosphate reserves to SCS but leads to alterations in gene expression of several metabolic and immunomodulatory pathways. These findings may offer important insight into reduced primary graft dysfunction observed in TCHP- hearts.
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Affiliation(s)
- Gaurav Sharma
- Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center, Dallas, Texas; Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Biomedical Engineering, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Ryan J Vela
- Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center, Dallas, Texas
| | - LaShondra Powell
- Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Stanislaw Deja
- Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Xiaorong Fu
- Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Shawn C Burgess
- Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Craig R Malloy
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Michael E Jessen
- Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Matthias Peltz
- Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center, Dallas, Texas.
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Zhang P, Wang J, Miao J, Zhu P. The dual role of tissue regulatory T cells in tissue repair: return to homeostasis or fibrosis. Front Immunol 2025; 16:1560578. [PMID: 40114929 PMCID: PMC11922884 DOI: 10.3389/fimmu.2025.1560578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Accepted: 02/18/2025] [Indexed: 03/22/2025] Open
Abstract
Tissue resident regulatory T cells (tissue Tregs) are vital for maintaining immune homeostasis and controlling inflammation. They aid in repairing damaged tissues and influencing the progression of fibrosis. However, despite extensive research on how tissue Tregs interact with immune and non-immune cells during tissue repair, their pro- and anti-fibrotic effects in chronic tissue injury remain unclear. Understanding how tissue Tregs interact with various cell types, as well as their roles in chronic injury and fibrosis, is crucial for uncovering the mechanisms behind these conditions. In this review, we describe the roles of tissue Tregs in repair and fibrosis across different tissues and explore potential strategies for regulating tissue homeostasis. These insights hold promise for providing new perspectives and approaches for the treatment of irreversible fibrotic diseases.
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Affiliation(s)
| | | | - Jinlin Miao
- Department of Clinical Immunology of Xijing Hospital and Department of Cell Biology of National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Ping Zhu
- Department of Clinical Immunology of Xijing Hospital and Department of Cell Biology of National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi’an, Shaanxi, China
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Devan J, Sandalova M, Bitterli P, Herger N, Mengis T, Brender K, Heggli I, Distler O, Dudli S. Massively parallel flow-cytometry-based screening of hematopoietic lineage cell populations from up to 25 donors simultaneously. Methods 2025; 234:45-53. [PMID: 39608688 DOI: 10.1016/j.ymeth.2024.11.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 11/16/2024] [Accepted: 11/26/2024] [Indexed: 11/30/2024] Open
Abstract
This study aimed to develop a method allowing high-dimensional and technically uniform screening of surface markers on cells of hematopoietic origin. High-dimensional screening of cell phenotypes is primarily the domain of single-cell RNA sequencing (RNAseq), which allows simultaneous analysis of the expression of thousands of genes in several thousands of cells. However, rare cell populations can often substantially impact tissue homeostasis or disease pathogenesis, and dysregulation of rare populations can easily be missed when only a few thousand cells are analyzed. With the presented methodological approach, it is possible to screen hundreds of markers on millions of cells in a technically uniform manner and thus identify and characterize changes in rare populations. We utilize the highly expressed markers CD45 on immune cells and CD71 on erythroid progenitors to create unique fluorescent barcodes on each of the 25 samples. Double-barcoded samples are co-stained with a broad immunophenotyping panel. The panel is designed in such a way that allows the addition of PE-labelled antibody, which was used for screening purposes. Multiplexed samples are divided into hundreds of aliquots and co-stained, each aliquot with a different PE-labelled antibody. Utilizing a broad immunophenotyping panel and machine-learning algorithms, we can predict the co-expression of hundreds of screened markers with a high degree of precision. This technique is suitable for screening immune cells in bone marrow from different locations, blood specimens, or any tissue with a substantial presence of immune cells, such as tumors or inflamed tissue areas in autoimmune conditions. It represents an approach that can significantly improve our ability to recognize dysregulated immune cell populations and, if needed, precisely target subsequent experiments covering lower cell counts such as RNAseq.
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Affiliation(s)
- Jan Devan
- Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Switzerland; Department of Physical Medicine and Rheumatology, Balgrist University Hospital, Balgrist Campus, University of Zurich, Zurich, Switzerland.
| | - Michaela Sandalova
- Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Switzerland; Department of Physical Medicine and Rheumatology, Balgrist University Hospital, Balgrist Campus, University of Zurich, Zurich, Switzerland
| | - Pamela Bitterli
- Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Switzerland; Department of Physical Medicine and Rheumatology, Balgrist University Hospital, Balgrist Campus, University of Zurich, Zurich, Switzerland
| | - Nick Herger
- Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Switzerland; Department of Physical Medicine and Rheumatology, Balgrist University Hospital, Balgrist Campus, University of Zurich, Zurich, Switzerland
| | - Tamara Mengis
- Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Switzerland; Department of Physical Medicine and Rheumatology, Balgrist University Hospital, Balgrist Campus, University of Zurich, Zurich, Switzerland
| | - Kenta Brender
- Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Switzerland; Department of Physical Medicine and Rheumatology, Balgrist University Hospital, Balgrist Campus, University of Zurich, Zurich, Switzerland
| | - Irina Heggli
- Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Switzerland; Department of Physical Medicine and Rheumatology, Balgrist University Hospital, Balgrist Campus, University of Zurich, Zurich, Switzerland
| | - Oliver Distler
- Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Switzerland; Department of Physical Medicine and Rheumatology, Balgrist University Hospital, Balgrist Campus, University of Zurich, Zurich, Switzerland
| | - Stefan Dudli
- Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Switzerland; Department of Physical Medicine and Rheumatology, Balgrist University Hospital, Balgrist Campus, University of Zurich, Zurich, Switzerland
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Akhtar S, Sagar K, Roy A, Hote MP, Arava S, Sharma A. CCR5-mediated homing of regulatory T cells and monocytic-myeloid derived suppressor cells to dysfunctional endothelium contributes to early atherosclerosis. Immunology 2024; 173:712-729. [PMID: 39256808 DOI: 10.1111/imm.13859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 08/23/2024] [Indexed: 09/12/2024] Open
Abstract
A disbalance between immune regulatory cells and inflammatory cells is known to drive atherosclerosis. However, the exact mechanism is not clear. Here, we investigated the homing of immune regulatory cells, mainly, regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) subsets in asymptomatic coronary artery disease (CAD) risk factor-exposed young individuals (dyslipidemia [DLP] group) and stable CAD patients (CAD group). Compared with healthy controls (HCs), Tregs frequency was reduced in both DLP and CAD groups but expressed high levels of CCR5 in both groups. The frequency of monocytic-myeloid-derived suppressor cells (M-MDSCs) was increased while polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) were decreased in CAD patients only. Interestingly, although unchanged in frequency, M-MDSCs of the DLP group expressed high levels of CCR5. Serum levels of chemokines (CCL5, CX3CL1, CCL26) and inflammatory cytokines (IL-6, IL-1β, IFN-γ, TNF-α) were higher in the DLP group. Stimulation with inflammatory cytokines augmented CCR5 expression in Tregs and M-MDSCs isolated from HCs. Activated endothelial cells showed elevated levels of CX3CL1 and CCL5 in vitro. Blocking CCR5 with D-Ala-peptide T-amide (DAPTA) increased Treg and M-MDSC frequency in C57Bl6 mice fed a high-fat diet. In accelerated atherosclerosis model, DAPTA treatment led to the formation of smooth muscle-rich plaque with less macrophages. Thus, we show that CCR5-CCL5 axis is instrumental in recruiting Tregs and M-MDSCs to dysfunctional endothelium in the asymptomatic phase of atherosclerosis contributing to atherosclerosis progression. Drugs targeting CCR5 in asymptomatic and CAD risk-factor/s-exposed individuals might be a novel therapeutic regime to diminish atherogenesis.
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Affiliation(s)
- Shamima Akhtar
- Department of Biochemistry, All India Institute of Medical Sciences, AIIMS, New Delhi, India
| | - Komal Sagar
- Department of Biochemistry, All India Institute of Medical Sciences, AIIMS, New Delhi, India
| | - Ambuj Roy
- Department of Cardiology, AIIMS, New Delhi, India
| | - Milind P Hote
- Department of Cardiothoracic and Vascular Surgery, AIIMS, New Delhi, India
| | | | - Alpana Sharma
- Department of Biochemistry, All India Institute of Medical Sciences, AIIMS, New Delhi, India
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7
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Juhasz V, Charlier FT, Zhao TX, Tsiantoulas D. Targeting the adaptive immune continuum in atherosclerosis and post-MI injury. Atherosclerosis 2024; 399:118616. [PMID: 39546915 DOI: 10.1016/j.atherosclerosis.2024.118616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 09/04/2024] [Accepted: 09/24/2024] [Indexed: 11/17/2024]
Abstract
Atherosclerotic disease is a cholesterol-rich lipoprotein particle-driven disease resulting in the formation of atherosclerotic plaques in large and medium size arteries. Rupture or erosion of atherosclerotic plaques can trigger the formation of a thrombus causing the obstruction of the blood flow in the coronary artery and thereby leading to myocardial infarction (MI). Inflammation is a crucial pillar of the mechanisms leading to atherosclerosis and governing the cardiac repair post-MI. Dissecting the complex and sophisticated networks of the immune responses underlying the formation of atherosclerotic plaques and affecting the healing of the heart after MI will allow the designing of highly precise immunomodulatory therapies for these settings. Notably, MI also accelerates atherosclerosis via modulating the response of the immune system. Therefore, for the identification of effective and safe therapeutic targets, it is critical to consider the inflammatory continuum that interconnects the two pathologies and identify immunomodulatory strategies that confer a protective effect in both settings or at least, affect each pathology independently. Adaptive immunity, which consists of B and T lymphocytes, is a major regulator of atherosclerosis and post-MI cardiac repair. Here, we review and discuss the effect of potential adaptive immunity-targeting therapies, such as cell-depleting therapies, in atherosclerosis and post-MI cardiac injury.
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Affiliation(s)
- Viktoria Juhasz
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Fiona T Charlier
- Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Tian X Zhao
- Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, Cambridge, United Kingdom; Department of Cardiology, Royal Papworth Hospital NHS Trust, Cambridge, United Kingdom
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Alexanian M, Padmanabhan A, Nishino T, Travers JG, Ye L, Pelonero A, Lee CY, Sadagopan N, Huang Y, Auclair K, Zhu A, An Y, Ekstrand CA, Martinez C, Teran BG, Flanigan WR, Kim CKS, Lumbao-Conradson K, Gardner Z, Li L, Costa MW, Jain R, Charo I, Combes AJ, Haldar SM, Pollard KS, Vagnozzi RJ, McKinsey TA, Przytycki PF, Srivastava D. Chromatin remodelling drives immune cell-fibroblast communication in heart failure. Nature 2024; 635:434-443. [PMID: 39443808 PMCID: PMC11698514 DOI: 10.1038/s41586-024-08085-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 09/19/2024] [Indexed: 10/25/2024]
Abstract
Chronic inflammation and tissue fibrosis are common responses that worsen organ function, yet the molecular mechanisms governing their cross-talk are poorly understood. In diseased organs, stress-induced gene expression changes fuel maladaptive cell state transitions1 and pathological interaction between cellular compartments. Although chronic fibroblast activation worsens dysfunction in the lungs, liver, kidneys and heart, and exacerbates many cancers2, the stress-sensing mechanisms initiating transcriptional activation of fibroblasts are poorly understood. Here we show that conditional deletion of the transcriptional co-activator Brd4 in infiltrating Cx3cr1+ macrophages ameliorates heart failure in mice and significantly reduces fibroblast activation. Analysis of single-cell chromatin accessibility and BRD4 occupancy in vivo in Cx3cr1+ cells identified a large enhancer proximal to interleukin-1β (IL-1β, encoded by Il1b), and a series of CRISPR-based deletions revealed the precise stress-dependent regulatory element that controls Il1b expression. Secreted IL-1β activated a fibroblast RELA-dependent (also known as p65) enhancer near the transcription factor MEOX1, resulting in a profibrotic response in human cardiac fibroblasts. In vivo, antibody-mediated IL-1β neutralization improved cardiac function and tissue fibrosis in heart failure. Systemic IL-1β inhibition or targeted Il1b deletion in Cx3cr1+ cells prevented stress-induced Meox1 expression and fibroblast activation. The elucidation of BRD4-dependent cross-talk between a specific immune cell subset and fibroblasts through IL-1β reveals how inflammation drives profibrotic cell states and supports strategies that modulate this process in heart disease and other chronic inflammatory disorders featuring tissue remodelling.
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Affiliation(s)
- Michael Alexanian
- Gladstone Institutes, San Francisco, CA, USA.
- Roddenberry Center for Stem Cell Biology at Gladstone Institutes, San Francisco, CA, USA.
- Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.
| | - Arun Padmanabhan
- Gladstone Institutes, San Francisco, CA, USA
- Roddenberry Center for Stem Cell Biology at Gladstone Institutes, San Francisco, CA, USA
- Department of Medicine, Division of Cardiology, University of California, San Francisco, San Francisco, CA, USA
- Chan Zuckerberg Biohub San Francisco, San Francisco, CA, USA
| | - Tomohiro Nishino
- Gladstone Institutes, San Francisco, CA, USA
- Roddenberry Center for Stem Cell Biology at Gladstone Institutes, San Francisco, CA, USA
| | - Joshua G Travers
- Department of Medicine, Division of Cardiology and Consortium for Fibrosis Research & Translation, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Lin Ye
- Gladstone Institutes, San Francisco, CA, USA
- Roddenberry Center for Stem Cell Biology at Gladstone Institutes, San Francisco, CA, USA
| | - Angelo Pelonero
- Gladstone Institutes, San Francisco, CA, USA
- Roddenberry Center for Stem Cell Biology at Gladstone Institutes, San Francisco, CA, USA
| | - Clara Youngna Lee
- Gladstone Institutes, San Francisco, CA, USA
- Roddenberry Center for Stem Cell Biology at Gladstone Institutes, San Francisco, CA, USA
- Department of Medicine, Division of Cardiology, University of California, San Francisco, San Francisco, CA, USA
| | - Nandhini Sadagopan
- Gladstone Institutes, San Francisco, CA, USA
- Roddenberry Center for Stem Cell Biology at Gladstone Institutes, San Francisco, CA, USA
- Department of Medicine, Division of Cardiology, University of California, San Francisco, San Francisco, CA, USA
| | - Yu Huang
- Gladstone Institutes, San Francisco, CA, USA
- Roddenberry Center for Stem Cell Biology at Gladstone Institutes, San Francisco, CA, USA
| | - Kirsten Auclair
- Gladstone Institutes, San Francisco, CA, USA
- Roddenberry Center for Stem Cell Biology at Gladstone Institutes, San Francisco, CA, USA
| | - Ada Zhu
- Gladstone Institutes, San Francisco, CA, USA
- Roddenberry Center for Stem Cell Biology at Gladstone Institutes, San Francisco, CA, USA
| | - Yuqian An
- Gladstone Institutes, San Francisco, CA, USA
- Roddenberry Center for Stem Cell Biology at Gladstone Institutes, San Francisco, CA, USA
| | - Christina A Ekstrand
- CoLabs initiative, University of California, San Francisco, CA, USA
- ImmunoX initiative, University of California, San Francisco, CA, USA
| | - Cassandra Martinez
- Gladstone Institutes, San Francisco, CA, USA
- Roddenberry Center for Stem Cell Biology at Gladstone Institutes, San Francisco, CA, USA
| | - Barbara Gonzalez Teran
- Gladstone Institutes, San Francisco, CA, USA
- Roddenberry Center for Stem Cell Biology at Gladstone Institutes, San Francisco, CA, USA
| | - Will R Flanigan
- Gladstone Institutes, San Francisco, CA, USA
- UC Berkeley-UCSF Joint Program in Bioengineering, Berkeley, CA, USA
| | - Charis Kee-Seon Kim
- Gladstone Institutes, San Francisco, CA, USA
- Roddenberry Center for Stem Cell Biology at Gladstone Institutes, San Francisco, CA, USA
| | - Koya Lumbao-Conradson
- Department of Medicine, Division of Cardiology and Consortium for Fibrosis Research & Translation, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Zachary Gardner
- Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA
- Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Cell Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Li Li
- Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA
- Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Cell Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Mauro W Costa
- Gladstone Institutes, San Francisco, CA, USA
- Roddenberry Center for Stem Cell Biology at Gladstone Institutes, San Francisco, CA, USA
| | - Rajan Jain
- Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA
- Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Cell Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | | | - Alexis J Combes
- CoLabs initiative, University of California, San Francisco, CA, USA
- ImmunoX initiative, University of California, San Francisco, CA, USA
- Department of Pathology, University of California, San Francisco, CA, USA
| | - Saptarsi M Haldar
- Gladstone Institutes, San Francisco, CA, USA
- Department of Medicine, Division of Cardiology, University of California, San Francisco, San Francisco, CA, USA
- Amgen Research, Cardiometabolic Disorders, South San Francisco, CA, USA
| | - Katherine S Pollard
- Gladstone Institutes, San Francisco, CA, USA
- Chan Zuckerberg Biohub San Francisco, San Francisco, CA, USA
- Institute for Computational Health Sciences, University of California, San Francisco, San Francisco, CA, USA
- Department of Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, CA, USA
- Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA
| | - Ronald J Vagnozzi
- Department of Medicine, Division of Cardiology and Consortium for Fibrosis Research & Translation, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Timothy A McKinsey
- Department of Medicine, Division of Cardiology and Consortium for Fibrosis Research & Translation, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Pawel F Przytycki
- Gladstone Institutes, San Francisco, CA, USA
- Faculty of Computing & Data Sciences, Boston University, Boston, MA, USA
| | - Deepak Srivastava
- Gladstone Institutes, San Francisco, CA, USA
- Roddenberry Center for Stem Cell Biology at Gladstone Institutes, San Francisco, CA, USA
- Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA
- Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA
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Liu L, Hu J, Lei H, Qin H, Wang C, Gui Y, Xu D. Regulatory T Cells in Pathological Cardiac Hypertrophy: Mechanisms and Therapeutic Potential. Cardiovasc Drugs Ther 2024; 38:999-1015. [PMID: 37184744 DOI: 10.1007/s10557-023-07463-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/29/2023] [Indexed: 05/16/2023]
Abstract
BACKGROUND Pathological cardiac hypertrophy is linked to immune-inflammatory injury, and regulatory T cells (Tregs) play a crucial role in suppressing immune-inflammatory responses. However, the precise role of Tregs in pathological cardiac hypertrophy remains unclear. OBJECTIVE To summarize the current knowledge on the role and mechanisms of Tregs in pathological cardiac hypertrophy and explore their perspectives and challenges as a new therapeutic approach. RESULTS Treg cells may play an important protective role in pressure overload (hypertension, aortic stenosis), myocardial infarction, metabolic disorders (diabetes, obesity), acute myocarditis, cardiomyopathy (hypertrophic cardiomyopathy, storage diseases), and chronic obstructive pulmonary disease-related pathological cardiac hypertrophy. Although some challenges remain, the safety and efficacy of Treg-based therapies have been confirmed in some clinical trials, and engineered antigen-specific Treg cells may have better clinical application prospects due to stronger immunosuppressive function and stability. CONCLUSION Targeting the immune-inflammatory response via Treg-based therapies might provide a promising and novel future approach to the prevention and treatment of pathological cardiac hypertrophy.
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Affiliation(s)
- Leiling Liu
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Jiahui Hu
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Hao Lei
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Huali Qin
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Chunfang Wang
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Yajun Gui
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Danyan Xu
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
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10
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Urszula Ł, Ulana J, Bartosz S, Maja O, Małgorzata M, Monika RS. Exploring CCR5 + T regulatory cell subset dysfunction in type 1 diabetes patients: implications for immune regulation. Immunol Res 2024; 72:1061-1070. [PMID: 38937380 PMCID: PMC11564404 DOI: 10.1007/s12026-024-09508-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Accepted: 06/13/2024] [Indexed: 06/29/2024]
Abstract
T regulatory lymphocytes (Treg) expressing CCR5 exhibit strong suppression activity in various autoimmune disorders. However, there remains a lack of comprehensive understanding regarding their involvement in the development of type 1 diabetes (T1D). In this study, we examined the role of the CCR5/CCL5 axis in regulating inflammatory response and its impact on regulatory T cells in type 1 diabetes (T1D). We hypothesize that dysregulation of the CCR5/CCL5 axis contributes to the development and progression of T1D through modulation of Treg-dependent immune responses. We analyzed the expression levels of CCR5 on Tregs isolated from individuals with T1D, as well as the plasma concentration of its main ligands. We found that Tregs from T1D patients exhibited decreased expression of CCR5 compared to healthy controls. Additionally, we observed a correlation between the expression levels of CCR5 on Tregs and their immunosuppressive function in T1D patients. Our results indicate the impaired migratory capacity of CCR5 + Tregs, suggesting a possible link between the dysregulation of the CCR5/CCL5 axis and impaired immune regulation in T1D. In line with previous studies, our findings support the notion that dysregulation of the CCR5/CCL5 axis contributes to the development and progression of type 1 diabetes (T1D) by modulating Treg-dependent immune responses. The decreased expression of CCR5 on Tregs in T1D patients suggests a potential impairment in the migratory capacity of these cells, which could compromise their ability to suppress autoreactive T cells and maintain immune homeostasis. Furthermore, our study highlights the importance of CCR5 as a biomarker for identifying dysfunctional Tregs in T1D.
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Affiliation(s)
- Ławrynowicz Urszula
- Department of Medical Immunology, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland.
| | - Juhas Ulana
- Division of Bioenergetics and Physiology of Exercise, Faculty of Health Sciences, Medical University of Gdańsk, Gdańsk, Poland
| | - Słomiński Bartosz
- Department of Medical Immunology, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Okońska Maja
- Department of Paediatrics, Diabetology and Endocrinology, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Myśliwiec Małgorzata
- Department of Paediatrics, Diabetology and Endocrinology, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
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11
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Jin S, Wan S, Xiong R, Li Y, Dong T, Guan C. The role of regulatory T cells in vitiligo and therapeutic advances: a mini-review. Inflamm Res 2024; 73:1311-1332. [PMID: 38839628 DOI: 10.1007/s00011-024-01900-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 05/21/2024] [Accepted: 05/29/2024] [Indexed: 06/07/2024] Open
Abstract
BACKGROUND Regulatory T cells (Tregs) play vital roles in controlling immune reactions and maintaining immune tolerance in the body. The targeted destruction of epidermal melanocytes by activated CD8+T cells is a key event in the development of vitiligo. However, Tregs may exert immunosuppressive effects on CD8+T cells, which could be beneficial in treating vitiligo. METHODS A comprehensive search of PubMed and Web of Science was conducted to gather information on Tregs and vitiligo. RESULTS In vitiligo, there is a decrease in Treg numbers and impaired Treg functions, along with potential damage to Treg-related signaling pathways. Increasing Treg numbers and enhancing Treg function could lead to immunosuppressive effects on CD8+T cells. Recent research progress on Tregs in vitiligo has been summarized, highlighting various Treg-related therapies being investigated for clinical use. The current status of Treg-related therapeutic strategies and potential future directions for vitiligo treatment are also discussed. CONCLUSIONS A deeper understanding of Tregs will be crucial for advancing Treg-related drug discovery and treatment development in vitiligo.
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Affiliation(s)
- Shiyu Jin
- Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310009, China
| | - Sheng Wan
- Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310009, China
- Department of Dermatology, Hangzhou Third People's Hospital, Hangzhou, 310009, China
| | - Renxue Xiong
- Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310009, China
- Department of Dermatology, Hangzhou Third People's Hospital, Hangzhou, 310009, China
| | - Yujie Li
- Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310009, China
| | - Tingru Dong
- Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310009, China
| | - Cuiping Guan
- Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310009, China.
- Department of Dermatology, Hangzhou Third People's Hospital, Hangzhou, 310009, China.
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12
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Hilgendorf I, Frantz S, Frangogiannis NG. Repair of the Infarcted Heart: Cellular Effectors, Molecular Mechanisms and Therapeutic Opportunities. Circ Res 2024; 134:1718-1751. [PMID: 38843294 PMCID: PMC11164543 DOI: 10.1161/circresaha.124.323658] [Citation(s) in RCA: 27] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Accepted: 05/08/2024] [Indexed: 06/12/2024]
Abstract
The adult mammalian heart has limited endogenous regenerative capacity and heals through the activation of inflammatory and fibrogenic cascades that ultimately result in the formation of a scar. After infarction, massive cardiomyocyte death releases a broad range of damage-associated molecular patterns that initiate both myocardial and systemic inflammatory responses. TLRs (toll-like receptors) and NLRs (NOD-like receptors) recognize damage-associated molecular patterns (DAMPs) and transduce downstream proinflammatory signals, leading to upregulation of cytokines (such as interleukin-1, TNF-α [tumor necrosis factor-α], and interleukin-6) and chemokines (such as CCL2 [CC chemokine ligand 2]) and recruitment of neutrophils, monocytes, and lymphocytes. Expansion and diversification of cardiac macrophages in the infarcted heart play a major role in the clearance of the infarct from dead cells and the subsequent stimulation of reparative pathways. Efferocytosis triggers the induction and release of anti-inflammatory mediators that restrain the inflammatory reaction and set the stage for the activation of reparative fibroblasts and vascular cells. Growth factor-mediated pathways, neurohumoral cascades, and matricellular proteins deposited in the provisional matrix stimulate fibroblast activation and proliferation and myofibroblast conversion. Deposition of a well-organized collagen-based extracellular matrix network protects the heart from catastrophic rupture and attenuates ventricular dilation. Scar maturation requires stimulation of endogenous signals that inhibit fibroblast activity and prevent excessive fibrosis. Moreover, in the mature scar, infarct neovessels acquire a mural cell coat that contributes to the stabilization of the microvascular network. Excessive, prolonged, or dysregulated inflammatory or fibrogenic cascades accentuate adverse remodeling and dysfunction. Moreover, inflammatory leukocytes and fibroblasts can contribute to arrhythmogenesis. Inflammatory and fibrogenic pathways may be promising therapeutic targets to attenuate heart failure progression and inhibit arrhythmia generation in patients surviving myocardial infarction.
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Affiliation(s)
- Ingo Hilgendorf
- Department of Cardiology and Angiology, University Heart Center Freiburg-Bad Krozingen and Faculty of Medicine at the University of Freiburg, Freiburg, Germany
| | - Stefan Frantz
- Medizinische Klinik und Poliklinik I, Universitätsklinikum Würzburg, Würzburg, Germany
| | - Nikolaos G Frangogiannis
- The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx NY
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13
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Lin Y, Liu S, Sun Y, Chen C, Yang S, Pei G, Lin M, Yu J, Liu X, Wang H, Long J, Yan Q, Liang J, Yao J, Yi F, Meng L, Tan Y, Chen N, Yang Y, Ai Q. CCR5 and inflammatory storm. Ageing Res Rev 2024; 96:102286. [PMID: 38561044 DOI: 10.1016/j.arr.2024.102286] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 03/15/2024] [Accepted: 03/25/2024] [Indexed: 04/04/2024]
Abstract
Chemokines and their corresponding receptors play crucial roles in orchestrating inflammatory and immune responses, particularly in the context of pathological conditions disrupting the internal environment. Among these receptors, CCR5 has garnered considerable attention due to its significant involvement in the inflammatory cascade, serving as a pivotal mediator of neuroinflammation and other inflammatory pathways associated with various diseases. However, a notable gap persists in comprehending the intricate mechanisms governing the interplay between CCR5 and its ligands across diverse and intricate inflammatory pathologies. Further exploration is warranted, especially concerning the inflammatory cascade instigated by immune cell infiltration and the precise binding sites within signaling pathways. This study aims to illuminate the regulatory axes modulating signaling pathways in inflammatory cells by providing a comprehensive overview of the pathogenic processes associated with CCR5 and its ligands across various disorders. The primary focus lies on investigating the pathomechanisms associated with CCR5 in disorders related to neuroinflammation, alongside the potential impact of aging on these processes and therapeutic interventions. The discourse culminates in addressing current challenges and envisaging potential future applications, advocating for innovative research endeavors to advance our comprehension of this realm.
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Affiliation(s)
- Yuting Lin
- Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Shasha Liu
- Department of Pharmacy, Changsha Hospital for Matemal&Child Health Care Affiliated to Hunan Normal University, Changsha 410007, China
| | - Yang Sun
- Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Chen Chen
- Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou 730000, China
| | - Songwei Yang
- Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Gang Pei
- Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Meiyu Lin
- Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Jingbo Yu
- Technology Innovation Center/National Key Laboratory Breeding Base of Chinese Medicine Powders and Innovative Drugs, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Xuan Liu
- Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Huiqin Wang
- Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Junpeng Long
- Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Qian Yan
- Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Jinping Liang
- Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Jiao Yao
- Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Fan Yi
- Key Laboratory of Cosmetic, China National Light Industry, Beijing Technology and Business University, Beijing 100048, China
| | - Lei Meng
- Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Yong Tan
- Nephrology Department, Xiangtan Central Hospital, Xiangtan 411100, China
| | - Naihong Chen
- Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China; State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
| | - Yantao Yang
- Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China.
| | - Qidi Ai
- Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China.
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14
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Huang M, Huiskes FG, de Groot NMS, Brundel BJJM. The Role of Immune Cells Driving Electropathology and Atrial Fibrillation. Cells 2024; 13:311. [PMID: 38391924 PMCID: PMC10886649 DOI: 10.3390/cells13040311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 02/02/2024] [Accepted: 02/04/2024] [Indexed: 02/24/2024] Open
Abstract
Atrial fibrillation (AF) is the most common progressive cardiac arrhythmia worldwide and entails serious complications including stroke and heart failure. Despite decades of clinical research, the current treatment of AF is suboptimal. This is due to a lack of knowledge on the mechanistic root causes of AF. Prevailing theories indicate a key role for molecular and structural changes in driving electrical conduction abnormalities in the atria and as such triggering AF. Emerging evidence indicates the role of the altered atrial and systemic immune landscape in driving this so-called electropathology. Immune cells and immune markers play a central role in immune remodeling by exhibiting dual facets. While the activation and recruitment of immune cells contribute to maintaining atrial stability, the excessive activation and pronounced expression of immune markers can foster AF. This review delineates shifts in cardiac composition and the distribution of immune cells in the context of cardiac health and disease, especially AF. A comprehensive exploration of the functions of diverse immune cell types in AF and other cardiac diseases is essential to unravel the intricacies of immune remodeling. Usltimately, we delve into clinical evidence showcasing immune modifications in both the atrial and systemic domains among AF patients, aiming to elucidate immune markers for therapy and diagnostics.
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Affiliation(s)
- Mingxin Huang
- Department of Physiology, Amsterdam UMC, Location Vrije Universiteit, Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, 1081 HZ Amsterdam, The Netherlands; (M.H.); (F.G.H.)
- Department of Cardiology, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands;
| | - Fabries G. Huiskes
- Department of Physiology, Amsterdam UMC, Location Vrije Universiteit, Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, 1081 HZ Amsterdam, The Netherlands; (M.H.); (F.G.H.)
| | | | - Bianca J. J. M. Brundel
- Department of Physiology, Amsterdam UMC, Location Vrije Universiteit, Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, 1081 HZ Amsterdam, The Netherlands; (M.H.); (F.G.H.)
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15
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Schauren JDS, de Oliveira AH, Consiglio CR, Monticielo OA, Xavier RM, Nunes NS, Ellwanger JH, Chies JAB. CCR5 promoter region polymorphisms in systemic lupus erythematosus. Int J Immunogenet 2024; 51:20-31. [PMID: 37984413 DOI: 10.1111/iji.12646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 10/26/2023] [Accepted: 11/09/2023] [Indexed: 11/22/2023]
Abstract
This study investigated the impacts of CCR5 promoter region polymorphisms on the development of systemic lupus erythematosus (SLE) by comparing CCR5 genotypes and haplotypes from SLE patients with ethnically matched controls. A total of 382 SLE patients (289 European-derived and 93 African-derived) and 375 controls (243 European-derived and 132 African-derived) were genotyped for the CCR2-64I G > A (rs1799864), CCR5-59353 C > T (rs1799988), CCR5-59356 C > T (rs41469351), CCR5-59402 A > G (rs1800023) and CCR5-59653 C > T (rs1800024) polymorphisms through polymerase chain reaction-restriction fragment length polymorphism and direct sequencing. Previous data from CCR5Δ32 analysis was included in the study to infer the CCR5 haplotypes and as a possible confounding factor in the binary logistic regression. European-derived patients showed a higher frequency of CCR5 wild-type genotype (conversely, a reduced frequency of Δ32 allele) and a reduced frequency of the HHG*2 haplotype compared to controls; both factors significantly affecting disease risk [p = .003 (OR 3.5, 95%CI 1.6-7.5) and 2.0% vs. 7.2% (residual p = 2.9E - 5), respectively]. Additionally, the HHA/HHB, HHC and HHG*2 haplotype frequencies differed between African-derived patients and controls [10% vs. 20.5% (residual p = .003), 29.4% vs. 17.4% (residual p = .003) and 3.9% vs. 0.8% (residual p = .023), respectively]. Considering the clinical manifestations of the disease, the CCR5Δ32 presence was confirmed as a susceptibility factor to class IV nephritis in the African-derived group and when all patients were grouped for comparison [pcorrected = .012 (OR 3.0; 95%CI 3.0-333.3) and pcorrected = .0006 (OR 6.8; 95%CI 1.9-24.8), respectively]. In conclusion, this study indicates that CCR5 promoter polymorphisms are important disease modifiers in SLE. Present data reinforces the CCR5Δ32 polymorphism as a protective factor for the development of the disease in European-derived patients and as a susceptibility factor for class IV nephritis in African-derived patients. Furthermore, we also described a reduced frequency of HHA/HHB and an increased frequency of HHC and HHG*2 haplotypes in African-derived patients, which could modify the CCR5 protein expression in specific cell subsets.
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Affiliation(s)
- Juliana da Silveira Schauren
- Laboratory of Immunobiology and Immunogenetics, Department of Genetics, Postgraduate Program in Genetics and Molecular Biology (PPGBM), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil
| | - Amanda Henrique de Oliveira
- Laboratory of Immunobiology and Immunogenetics, Department of Genetics, Postgraduate Program in Genetics and Molecular Biology (PPGBM), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil
- Postgraduate Program in Gastroenterology and Hepatology Sciences, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil
| | - Camila Rosat Consiglio
- Laboratory of Immunobiology and Immunogenetics, Department of Genetics, Postgraduate Program in Genetics and Molecular Biology (PPGBM), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil
| | - Odirlei André Monticielo
- Division of Rheumatology, Department of Internal Medicine, Hospital de Clínicas de Porto Alegre (HCPA), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil
| | - Ricardo Machado Xavier
- Division of Rheumatology, Department of Internal Medicine, Hospital de Clínicas de Porto Alegre (HCPA), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil
| | - Natália Schneider Nunes
- Postgraduate Program in Gastroenterology and Hepatology Sciences, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Joel Henrique Ellwanger
- Laboratory of Immunobiology and Immunogenetics, Department of Genetics, Postgraduate Program in Genetics and Molecular Biology (PPGBM), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil
| | - José Artur Bogo Chies
- Laboratory of Immunobiology and Immunogenetics, Department of Genetics, Postgraduate Program in Genetics and Molecular Biology (PPGBM), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil
- Postgraduate Program in Gastroenterology and Hepatology Sciences, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil
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Li J, Gong Y, Wang Y, Huang H, Du H, Cheng L, Ma C, Cai Y, Han H, Tao J, Li G, Cheng P. Classification of regulatory T cells and their role in myocardial ischemia-reperfusion injury. J Mol Cell Cardiol 2024; 186:94-106. [PMID: 38000204 DOI: 10.1016/j.yjmcc.2023.11.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 11/14/2023] [Accepted: 11/14/2023] [Indexed: 11/26/2023]
Abstract
Myocardial ischemia-reperfusion injury (MIRI) is closely related to the final infarct size in acute myocardial infarction (AMI). Therefore, reducing MIRI can effectively improve the prognosis of AMI patients. At the same time, the healing process after AMI is closely related to the local inflammatory microenvironment. Regulatory T cells (Tregs) can regulate various physiological and pathological immune inflammatory responses and play an important role in regulating the immune inflammatory response after AMI. However, different subtypes of Tregs have different effects on MIRI, and the same subtype of Tregs may also have different effects at different stages of MIRI. This article systematically reviews the classification and function of Tregs, as well as the role of various subtypes of Tregs in MIRI. A comprehensive understanding of the role of each subtype of Tregs can help design effective methods to control immune reactions, reduce MIRI, and provide new potential therapeutic options for AMI.
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Affiliation(s)
- Junlin Li
- Institute of Cardiovascular Diseases & Department of Cardiology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China; Department of Cardiology, The Second People's Hospital of Neijiang, Neijiang 641100, China
| | - Yajun Gong
- Institute of Cardiovascular Diseases & Department of Cardiology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Yiren Wang
- Institute of Cardiovascular Diseases & Department of Cardiology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Huihui Huang
- Institute of Cardiovascular Diseases & Department of Cardiology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Huan Du
- Institute of Cardiovascular Diseases & Department of Cardiology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Lianying Cheng
- Department of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Cui Ma
- Department of Mathematics, Army Medical University, Chongqing 400038, China
| | - Yongxiang Cai
- Institute of Cardiovascular Diseases & Department of Cardiology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Hukui Han
- Institute of Cardiovascular Diseases & Department of Cardiology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Jianhong Tao
- Institute of Cardiovascular Diseases & Department of Cardiology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Gang Li
- Institute of Cardiovascular Diseases & Department of Cardiology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Panke Cheng
- Institute of Cardiovascular Diseases & Department of Cardiology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China; Ultrasound in Cardiac Electrophysiology and Biomechanics Key Laboratory of Sichuan Province, Chengdu 610072, China.
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17
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Sikking MA, Stroeks SL, Marelli-Berg F, Heymans SR, Ludewig B, Verdonschot JA. Immunomodulation of Myocardial Fibrosis. JACC Basic Transl Sci 2023; 8:1477-1488. [PMID: 38093747 PMCID: PMC10714184 DOI: 10.1016/j.jacbts.2023.03.015] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 03/06/2023] [Accepted: 03/07/2023] [Indexed: 06/27/2024]
Abstract
Immunotherapy is a potential cornerstone in the treatment of myocardial fibrosis. During a myocardial insult or heart failure, danger signals stimulate innate immune cells to produce chemokines and profibrotic cytokines, which initiate self-escalating inflammatory processes by attracting and stimulating adaptive immune cells. Stimulation of fibroblasts by inflammatory processes and the need to replace damaged cardiomyocytes fosters reshaping of the cardiac fibroblast landscape. In this review, we discuss new immunomodulatory strategies that manipulate and direct cardiac fibroblast activation and differentiation. In particular, we highlight immunomodulatory strategies that target fibroblasts such as chimeric antigen receptor T cells, interleukin-11, and invariant natural killer T-cells. Moreover, we discuss the potential of manipulating both innate and adaptive immune system components for the translation into clinical validation. Clearly, multiple pathways should be considered to develop innovative approaches to ameliorate myocardial fibrosis and hence to reduce the risk of heart failure.
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Affiliation(s)
- Maurits A. Sikking
- Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, the Netherlands
| | - Sophie L.V.M. Stroeks
- Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, the Netherlands
| | - Federica Marelli-Berg
- William Harvey Research Institute, Queen Mary University of London, London, United Kingdom
| | - Stephane R.B. Heymans
- Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, the Netherlands
- Department of Cardiovascular Research, University of Leuven, Leuven, Belgium
| | - Burkhard Ludewig
- Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland
- Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland
| | - Job A.J. Verdonschot
- Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, the Netherlands
- Department of Clinical Genetics, Maastricht University Medical Center (MUMC), Maastricht, the Netherlands
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18
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Francisco J, Del Re DP. Inflammation in Myocardial Ischemia/Reperfusion Injury: Underlying Mechanisms and Therapeutic Potential. Antioxidants (Basel) 2023; 12:1944. [PMID: 38001797 PMCID: PMC10669026 DOI: 10.3390/antiox12111944] [Citation(s) in RCA: 51] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 10/23/2023] [Accepted: 10/27/2023] [Indexed: 11/26/2023] Open
Abstract
Acute myocardial infarction (MI) occurs when blood flow to the myocardium is restricted, leading to cardiac damage and massive loss of viable cardiomyocytes. Timely restoration of coronary flow is considered the gold standard treatment for MI patients and limits infarct size; however, this intervention, known as reperfusion, initiates a complex pathological process that somewhat paradoxically also contributes to cardiac injury. Despite being a sterile environment, ischemia/reperfusion (I/R) injury triggers inflammation, which contributes to infarct expansion and subsequent cardiac remodeling and wound healing. The immune response is comprised of subsets of both myeloid and lymphoid-derived cells that act in concert to modulate the pathogenesis and resolution of I/R injury. Multiple mechanisms, including altered metabolic status, regulate immune cell activation and function in the setting of acute MI, yet our understanding remains incomplete. While numerous studies demonstrated cardiac benefit following strategies that target inflammation in preclinical models, therapeutic attempts to mitigate I/R injury in patients were less successful. Therefore, further investigation leveraging emerging technologies is needed to better characterize this intricate inflammatory response and elucidate its influence on cardiac injury and the progression to heart failure.
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Affiliation(s)
| | - Dominic P. Del Re
- Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
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19
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Jeyalan V, Austin D, Loh SX, Wangsaputra VK, Spyridopoulos I. Fractalkine/CX 3CR1 in Dilated Cardiomyopathy: A Potential Future Target for Immunomodulatory Therapy? Cells 2023; 12:2377. [PMID: 37830591 PMCID: PMC10571889 DOI: 10.3390/cells12192377] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 09/22/2023] [Accepted: 09/26/2023] [Indexed: 10/14/2023] Open
Abstract
Dilated cardiomyopathy (DCM) is a cardiac condition with structural and functional impairment, where either the left ventricle or both ventricular chambers are enlarged, coinciding with reduced systolic pump function (reduced ejection fraction, rEF). The prevalence of DCM is more than 1:250 individuals, and mortality largely due to heart failure in two-third of cases, and sudden cardiac death in one-third of patients. Damage to the myocardium, whether from a genetic or environmental cause such as viruses, triggers inflammation and recruits immune cells to the heart to repair the myocardium. Examination of myocardial biopsy tissue often reveals an inflammatory cell infiltrate, T lymphocyte (T cell) infiltration, or other activated immune cells. Despite medical therapy, adverse outcomes for DCM remain. The evidence base and existing literature suggest that upregulation of CX3CR1, migration of immune cells, together with cytomegalovirus (CMV) seropositivity is associated with worse outcomes in patients with dilated cardiomyopathy. We hypothesise that this potentially occurs through cardiac inflammation and fibrosis, resulting in adverse remodelling. Immune modulators to target this pathway may potentially improve outcomes above and beyond current guideline-recommended therapy.
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Affiliation(s)
- Visvesh Jeyalan
- Academic Cardiovascular Unit, The James Cook University Hospital, Middlesbrough TS4 3BW, UK; (V.J.); (D.A.)
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK;
| | - David Austin
- Academic Cardiovascular Unit, The James Cook University Hospital, Middlesbrough TS4 3BW, UK; (V.J.); (D.A.)
- Population Health Science Institute, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
| | - Shu Xian Loh
- Department of Cardiology, Freeman Hospital, Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne NE7 7DN, UK;
| | - Vincent Kharisma Wangsaputra
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK;
- Faculty of Medicine, Universitas Indonesia, Central Jakarta 10430, Indonesia
| | - Ioakim Spyridopoulos
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK;
- Department of Cardiology, Freeman Hospital, Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne NE7 7DN, UK;
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20
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Ni H, Chen Y. Differentiation, regulation and function of regulatory T cells in non-lymphoid tissues and tumors. Int Immunopharmacol 2023; 121:110429. [PMID: 37327512 DOI: 10.1016/j.intimp.2023.110429] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 05/22/2023] [Accepted: 05/30/2023] [Indexed: 06/18/2023]
Abstract
Regulatory T cells (Tregs) play a substantial role in inhibiting excessive immune response. A large number of studies have focused on the tissue homeostasis maintenance and remodeling characteristics of Tregs in non-lymphoid tissues, such as the skin, colon, lung, brain, muscle, and adipose tissues. Herein, we overview the kinetics of Treg migration to non-lymphoid tissues and adaptation to the specific tissue microenvironment through the development of tissue-specific chemokine receptors, transcription factors, and phenotypes. Additionally, tumor-infiltrating Tregs (Ti-Tregs) play an important role in tumor generation and immunotherapy resistance. The phenotypes of Ti-Tregs are related to the histological location of the tumor and there is a large overlap between the transcripts of Ti-Tregs and those of tissue-specific Tregs. We recapitulate the molecular underpinnings of tissue-specific Tregs, which might shed new light on Treg-based therapeutic targets and biomarkers for inflammatory diseases and cancer.
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Affiliation(s)
- Hongbo Ni
- The First Clinical Medicine Faculty, China Medical University, Shenyang 110001, China
| | - Yinghan Chen
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110001, China.
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21
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Chowkwale M, Lindsey ML, Saucerman JJ. Intercellular model predicts mechanisms of inflammation-fibrosis coupling after myocardial infarction. J Physiol 2023; 601:2635-2654. [PMID: 35862254 PMCID: PMC9859968 DOI: 10.1113/jp283346] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 07/18/2022] [Indexed: 01/25/2023] Open
Abstract
After myocardial infarction (MI), cardiac cells work together to regulate wound healing of the infarct. The pathological response to MI yields cardiac remodelling comprising inflammatory and fibrosis phases, and the interplay of cellular dynamics that underlies these phases has not been elucidated. This study developed a computational model to identify cytokine and cellular dynamics post-MI to predict mechanisms driving post-MI inflammation, resolution of inflammation, and scar formation. Additionally, this study evaluated the interdependence between inflammation and fibrosis. Our model bypassed limitations of in vivo approaches in achieving cellular specificity and performing specific perturbations such as global knockouts of chemical factors. The model predicted that inflammation is a graded response to initial infarct size that is amplified by a positive feedback loop between neutrophils and interleukin 1β (IL-1β). Resolution of inflammation was driven by degradation of IL-1β, matrix metalloproteinase 9, and transforming growth factor β (TGF-β), as well as apoptosis of neutrophils. Inflammation regulated TGFβ secretion directly through immune cell recruitment and indirectly through upregulation of macrophage phagocytosis. Lastly, we found that mature collagen deposition was an ultrasensitive switch in response to inflammation, which was amplified primarily by cardiac fibroblast proliferation. These findings describe the relationship between inflammation and fibrosis and highlight how the two responses work together post-MI. This model revealed that post-MI inflammation and fibrosis are dynamically coupled, which provides rationale for designing novel anti-inflammatory, pro-resolving or anti-fibrotic therapies that may improve the response to MI. KEY POINTS: Inflammation and matrix remodelling are two processes involved in wound healing after a heart attack. Cardiac cells work together to facilitate these processes; this is done by secreting cytokines that then regulate the cells themselves or other cells surrounding them. This study developed a computational model of the dynamics of cardiac cells and cytokines to predict mechanisms through which inflammation and matrix remodelling is regulated. We show the roles of various cytokines and signalling motifs in driving inflammation, resolution of inflammation and fibrosis. The novel concept of inflammation-fibrosis coupling, based on the model prediction that inflammation and fibrosis are dynamically coupled, provides rationale for future studies and for designing therapeutics to improve the response after a heart attack.
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Affiliation(s)
- Mukti Chowkwale
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA
| | - Merry L. Lindsey
- School of Graduate Studies and Research, Meharry Medical College, Nashville, TN
- Research Service, Nashville VA Medical Center, Nashville, TN
| | - Jeffrey J. Saucerman
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA
- Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA
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22
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Wang Y, Wang C, Shen L, Xu D. The Role of Regulatory T Cells in Heart Repair After Myocardial Infarction. J Cardiovasc Transl Res 2023:10.1007/s12265-022-10290-5. [PMID: 37347425 DOI: 10.1007/s12265-022-10290-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 07/04/2022] [Indexed: 06/23/2023]
Abstract
Myocardial infarction (MI) remains one of the leading causes of death worldwide. Inflammation and immune responses after MI are of significance to the adverse cardiac remodeling. Regulatory T cells (Tregs) play an important role in suppressing the immune response and thus benefit the post-MI remodeling. After MI, damaged cardiomyocytes may be replaced by scar tissue, leading to systolic and diastolic dysfunction and subsequently adverse remodeling. In this review, we provide an overview of the function and possible mechanisms of Tregs in post-MI heart repair. Specifically, after the occurrence of MI, Tregs infiltrated to peri-infarcted myocardium through CCR5 pathway, CXCR4-CXCL12 axis, and Hippo pathway. Normal functional Tregs can reduce the size of the MI area, improve heart function, and ameliorate myocardial remodeling by inhibiting proinflammatory cells accumulation, changing the proportion of macrophages phenotypes, improving myocardial fibrosis, protecting myocardial cells, and promoting angiogenesis. Eventually, Functional Tregs recruited into the heart can improve MI outcomes. Therefore, targeted therapies with Tregs might provide a promising approach to the treatment of MI remodeling.
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Affiliation(s)
- Yishu Wang
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, Hunan, China
| | - Chunfang Wang
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, Hunan, China
| | - Li Shen
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, Hunan, China
| | - Danyan Xu
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, Hunan, China.
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23
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Yin X, Yin X, Pan X, Zhang J, Fan X, Li J, Zhai X, Jiang L, Hao P, Wang J, Chen Y. Post-myocardial infarction fibrosis: Pathophysiology, examination, and intervention. Front Pharmacol 2023; 14:1070973. [PMID: 37056987 PMCID: PMC10086160 DOI: 10.3389/fphar.2023.1070973] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Accepted: 03/13/2023] [Indexed: 03/30/2023] Open
Abstract
Cardiac fibrosis plays an indispensable role in cardiac tissue homeostasis and repair after myocardial infarction (MI). The cardiac fibroblast-to-myofibroblast differentiation and extracellular matrix collagen deposition are the hallmarks of cardiac fibrosis, which are modulated by multiple signaling pathways and various types of cells in time-dependent manners. Our understanding of the development of cardiac fibrosis after MI has evolved in basic and clinical researches, and the regulation of fibrotic remodeling may facilitate novel diagnostic and therapeutic strategies, and finally improve outcomes. Here, we aim to elaborate pathophysiology, examination and intervention of cardiac fibrosis after MI.
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Affiliation(s)
- Xiaoying Yin
- Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Xinxin Yin
- Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Xin Pan
- Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Jingyu Zhang
- Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Xinhui Fan
- Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Jiaxin Li
- Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Xiaoxuan Zhai
- Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Lijun Jiang
- Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Panpan Hao
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Jiali Wang
- Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Yuguo Chen
- Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
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24
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Bioactive Compounds (BACs): A Novel Approach to Treat and Prevent Cardiovascular Diseases. Curr Probl Cardiol 2023; 48:101664. [PMID: 36841315 DOI: 10.1016/j.cpcardiol.2023.101664] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Accepted: 02/17/2023] [Indexed: 02/26/2023]
Abstract
Cardiovascular diseases (CVDs) are one of the leading disorders of serious death and cause huge economic loss to patients and society. It is estimated that about 18 million people have a high death ratio due to the incidence of CVDs such as (stroke, coronary heart disease, and non-ischemic heart failure). Bioactive compounds (BACs) are healthy nutritional ingredients providing beneficial effects and nutritional value to the human body. Epidemiological studies strongly shed light on several bioactive compounds that are favorable candidates for CVDs treatment. Globally, the high risk of CVDs and related results on human body parts made them a serious scenario in all communities. In this present review, we intend to collect previously published data concerned over the years concerning green-colored foods and their BACs that aim to work in the prevention, diagnosis, and/or systematic treating CVDs. We also comprehensively discussed the oral delivery of several bioactive compounds derived from fruits and vegetables and their bioavailability and physiological effects on human health. Moreover, their important characteristics, such as anti-inflammatory, lowering blood pressure, anti-obesity, antioxidant, anti-diabetics, lipid-lowering responses, improving atherosclerosis, and cardioprotective properties, will be elaborated further. More precisely, medicinal plants' advantages and multifaceted applications have been reported in this literature to treat CVDs. To the best of our knowledge, this is our first attempt that will open a new window in the area of CVDs with the opportunity to achieve a better prognosis and effective treatment for CVDs.
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25
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Alexanian M, Padmanabhan A, Nishino T, Travers JG, Ye L, Lee CY, Sadagopan N, Huang Y, Pelonero A, Auclair K, Zhu A, Teran BG, Flanigan W, Kim CKS, Lumbao-Conradson K, Costa M, Jain R, Charo I, Haldar SM, Pollard KS, Vagnozzi RJ, McKinsey TA, Przytycki PF, Srivastava D. Chromatin Remodeling Drives Immune-Fibroblast Crosstalk in Heart Failure Pathogenesis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.06.522937. [PMID: 36711864 PMCID: PMC9881961 DOI: 10.1101/2023.01.06.522937] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Chronic inflammation and tissue fibrosis are common stress responses that worsen organ function, yet the molecular mechanisms governing their crosstalk are poorly understood. In diseased organs, stress-induced changes in gene expression fuel maladaptive cell state transitions and pathological interaction between diverse cellular compartments. Although chronic fibroblast activation worsens dysfunction of lung, liver, kidney, and heart, and exacerbates many cancers, the stress-sensing mechanisms initiating the transcriptional activation of fibroblasts are not well understood. Here, we show that conditional deletion of the transcription co-activator Brd4 in Cx3cr1-positive myeloid cells ameliorates heart failure and is associated with a dramatic reduction in fibroblast activation. Analysis of single-cell chromatin accessibility and BRD4 occupancy in vivo in Cx3cr1-positive cells identified a large enhancer proximal to Interleukin-1 beta (Il1b), and a series of CRISPR deletions revealed the precise stress-dependent regulatory element that controlled expression of Il1b in disease. Secreted IL1B functioned non-cell autonomously to activate a p65/RELA-dependent enhancer near the transcription factor MEOX1, resulting in a profibrotic response in human cardiac fibroblasts. In vivo, antibody-mediated IL1B neutralization prevented stress-induced expression of MEOX1, inhibited fibroblast activation, and improved cardiac function in heart failure. The elucidation of BRD4-dependent crosstalk between a specific immune cell subset and fibroblasts through IL1B provides new therapeutic strategies for heart disease and other disorders of chronic inflammation and maladaptive tissue remodeling.
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Affiliation(s)
- Michael Alexanian
- Gladstone Institutes; San Francisco, CA, USA
- Roddenberry Center for Stem Cell Biology and Medicine at Gladstone Institutes; San Francisco, CA, USA
- Department of Pediatrics, University of California, San Francisco; San Francisco, CA, USA
| | - Arun Padmanabhan
- Gladstone Institutes; San Francisco, CA, USA
- Roddenberry Center for Stem Cell Biology and Medicine at Gladstone Institutes; San Francisco, CA, USA
- Department of Medicine, Division of Cardiology, University of California, San Francisco; San Francisco CA, USA
- Chan Zuckerberg Biohub; San Francisco, CA, USA
| | - Tomohiro Nishino
- Gladstone Institutes; San Francisco, CA, USA
- Roddenberry Center for Stem Cell Biology and Medicine at Gladstone Institutes; San Francisco, CA, USA
| | - Joshua G. Travers
- Department of Medicine, Division of Cardiology and Consortium for Fibrosis Research & Translation, University of Colorado Anschutz Medical Campus; Aurora, CO, USA
| | - Lin Ye
- Gladstone Institutes; San Francisco, CA, USA
- Roddenberry Center for Stem Cell Biology and Medicine at Gladstone Institutes; San Francisco, CA, USA
| | - Clara Youngna Lee
- Gladstone Institutes; San Francisco, CA, USA
- Roddenberry Center for Stem Cell Biology and Medicine at Gladstone Institutes; San Francisco, CA, USA
- Department of Medicine, Division of Cardiology, University of California, San Francisco; San Francisco CA, USA
| | - Nandhini Sadagopan
- Gladstone Institutes; San Francisco, CA, USA
- Roddenberry Center for Stem Cell Biology and Medicine at Gladstone Institutes; San Francisco, CA, USA
- Department of Medicine, Division of Cardiology, University of California, San Francisco; San Francisco CA, USA
| | - Yu Huang
- Gladstone Institutes; San Francisco, CA, USA
- Roddenberry Center for Stem Cell Biology and Medicine at Gladstone Institutes; San Francisco, CA, USA
| | - Angelo Pelonero
- Gladstone Institutes; San Francisco, CA, USA
- Roddenberry Center for Stem Cell Biology and Medicine at Gladstone Institutes; San Francisco, CA, USA
| | - Kirsten Auclair
- Gladstone Institutes; San Francisco, CA, USA
- Roddenberry Center for Stem Cell Biology and Medicine at Gladstone Institutes; San Francisco, CA, USA
| | - Ada Zhu
- Gladstone Institutes; San Francisco, CA, USA
- Roddenberry Center for Stem Cell Biology and Medicine at Gladstone Institutes; San Francisco, CA, USA
| | - Barbara Gonzalez Teran
- Gladstone Institutes; San Francisco, CA, USA
- Roddenberry Center for Stem Cell Biology and Medicine at Gladstone Institutes; San Francisco, CA, USA
| | - Will Flanigan
- Gladstone Institutes; San Francisco, CA, USA
- UC Berkeley-UCSF Joint Program in Bioengineering; Berkeley, CA, USA
| | - Charis Kee-Seon Kim
- Gladstone Institutes; San Francisco, CA, USA
- Roddenberry Center for Stem Cell Biology and Medicine at Gladstone Institutes; San Francisco, CA, USA
| | - Koya Lumbao-Conradson
- Department of Medicine, Division of Cardiology and Consortium for Fibrosis Research & Translation, University of Colorado Anschutz Medical Campus; Aurora, CO, USA
| | - Mauro Costa
- Gladstone Institutes; San Francisco, CA, USA
- Roddenberry Center for Stem Cell Biology and Medicine at Gladstone Institutes; San Francisco, CA, USA
| | - Rajan Jain
- Cardiovascular Institute, Epigenetics Institute, and Department of Medicine, Perelman School of Medicine, University of Pennsylvania; Philadelphia, PA, USA
| | | | - Saptarsi M. Haldar
- Gladstone Institutes; San Francisco, CA, USA
- Department of Medicine, Division of Cardiology, University of California, San Francisco; San Francisco CA, USA
- Amgen Research, Cardiometabolic Disorders; South San Francisco, CA, USA
| | - Katherine S. Pollard
- Gladstone Institutes; San Francisco, CA, USA
- Chan Zuckerberg Biohub; San Francisco, CA, USA
- Institute for Computational Health Sciences, University of California, San Francisco; San Francisco, CA, USA
- Department of Epidemiology & Biostatistics, University of California, San Francisco; San Francisco, CA, USA
- Institute for Human Genetics, University of California, San Francisco; San Francisco, CA, USA
| | - Ronald J. Vagnozzi
- Department of Medicine, Division of Cardiology and Consortium for Fibrosis Research & Translation, University of Colorado Anschutz Medical Campus; Aurora, CO, USA
| | - Timothy A. McKinsey
- Department of Medicine, Division of Cardiology and Consortium for Fibrosis Research & Translation, University of Colorado Anschutz Medical Campus; Aurora, CO, USA
| | - Pawel F. Przytycki
- Gladstone Institutes; San Francisco, CA, USA
- Faculty of Computing & Data Sciences, Boston University; Boston, MA, USA
| | - Deepak Srivastava
- Gladstone Institutes; San Francisco, CA, USA
- Roddenberry Center for Stem Cell Biology and Medicine at Gladstone Institutes; San Francisco, CA, USA
- Department of Pediatrics, University of California, San Francisco; San Francisco, CA, USA
- Department of Biochemistry and Biophysics, University of California, San Francisco; San Francisco, CA, USA
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26
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Humeres C, Venugopal H, Frangogiannis NG. The Role of Mechanosensitive Signaling Cascades in Repair and Fibrotic Remodeling of the Infarcted Heart. CARDIAC AND VASCULAR BIOLOGY 2023:61-100. [DOI: 10.1007/978-3-031-23965-6_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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27
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Wang X, Zhou H, Liu Q, Cheng P, Zhao T, Yang T, Zhao Y, Sha W, Zhao Y, Qu H. Targeting regulatory T cells for cardiovascular diseases. Front Immunol 2023; 14:1126761. [PMID: 36911741 PMCID: PMC9995594 DOI: 10.3389/fimmu.2023.1126761] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Accepted: 02/13/2023] [Indexed: 02/25/2023] Open
Abstract
Cardiovascular diseases (CVDs) are the leading cause of death and disability worldwide. The CVDs are accompanied by inflammatory progression, resulting in innate and adaptive immune responses. Regulatory T cells (Tregs) have an immunosuppressive function and are one of the subsets of CD4+T cells that play a crucial role in inflammatory diseases. Whether using Tregs as a biomarker for CVDs or targeting Tregs to exert cardioprotective functions by regulating immune balance, suppressing inflammation, suppressing cardiac and vascular remodeling, mediating immune tolerance, and promoting cardiac regeneration in the treatment of CVDs has become an emerging research focus. However, Tregs have plasticity, and this plastic Tregs lose immunosuppressive function and produce toxic effects on target organs in some diseases. This review aims to provide an overview of Tregs' role and related mechanisms in CVDs, and reports on the research of plasticity Tregs in CVDs, to lay a foundation for further studies targeting Tregs in the prevention and treatment of CVDs.
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Affiliation(s)
- Xinting Wang
- Institute of Cardiovascular Disease of Integrated Traditional Chinese and Western Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hua Zhou
- Institute of Cardiovascular Disease of Integrated Traditional Chinese and Western Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Department of Cardiovascular Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qian Liu
- Institute of Cardiovascular Disease of Integrated Traditional Chinese and Western Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Peipei Cheng
- Institute of Cardiovascular Disease of Integrated Traditional Chinese and Western Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tingyao Zhao
- Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tianshu Yang
- Department of Cardiovascular Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yue Zhao
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wanjing Sha
- Institute of Cardiovascular Disease of Integrated Traditional Chinese and Western Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yanyan Zhao
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Huiyan Qu
- Department of Cardiovascular Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Schumacher D, Curaj A, Staudt M, Simsekyilmaz S, Kanzler I, Boor P, Klinkhammer BM, Li X, Bucur O, Kaabi A, Xu Y, Zheng H, Nilcham P, Schuh A, Rusu M, Liehn EA. Endogenous Modulation of Extracellular Matrix Collagen during Scar Formation after Myocardial Infarction. Int J Mol Sci 2022; 23:ijms232314571. [PMID: 36498897 PMCID: PMC9741070 DOI: 10.3390/ijms232314571] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 11/18/2022] [Accepted: 11/19/2022] [Indexed: 11/24/2022] Open
Abstract
Myocardial infarction is remains the leading cause of death in developed countries. Recent data show that the composition of the extracellular matrix might differ despite similar heart function and infarction sizes. Because collagen is the main component of the extracellular matrix, we hypothesized that changes in inflammatory cell recruitment influence the synthesis of different collagen subtypes in myofibroblasts, thus changing the composition of the scar. We found that neutrophils sustain the proliferation of fibroblasts, remodeling, differentiation, migration and inflammation, predominantly by IL-1 and PPARγ pathways (n = 3). They also significantly inhibit the mRNA expression of fibrillar collagen, maintaining a reduced stiffness in isolated myofibroblasts (n = 4-5). Reducing the neutrophil infiltration in CCR1-/- resulted in increased mRNA expression of collagen 11, moderate expression of collagen 19 and low expression of collagen 13 and 26 in the scar 4 weeks post infarction compared with other groups (n = 3). Mononuclear cells increased the synthesis of all collagen subtypes and upregulated the NF-kB, angiotensin II and PPARδ pathways (n = 3). They increased the synthesis of collagen subtypes 1, 3, 5, 16 and 23 but reduced the expression of collagens 5 and 16 (n = 3). CCR2-/- scar tissue showed higher levels of collagen 13 (n = 3), in association with a significant reduction in stiffness (n = 4-5). Upregulation of the inflammation-related genes in myofibroblasts mostly modulated the fibrillar collagen subtypes, with less effect on the FACIT, network-forming and globular subtypes (n = 3). The upregulation of proliferation and differentiation genes in myofibroblasts seemed to be associated only with the fibrillar collagen subtype, whereas angiogenesis-related genes are associated with fibrillar, network-forming and multiplexin subtypes. In conclusion, although we intend for our findings to deepen the understanding of the mechanism of healing after myocardial infarction and scar formation, the process of collagen synthesis is highly complex, and further intensive investigation is needed to put together all the missing puzzle pieces in this still incipient knowledge process.
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Affiliation(s)
- David Schumacher
- Department of Anesthesiology, University Hospital, RWTH Aachen University, 52074 Aachen, Germany
- Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, 52074 Aachen, Germany
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074 Aachen, Germany
| | - Adelina Curaj
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074 Aachen, Germany
- Department for Cardiology, Angiology and Internal Intensive Care, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany
| | - Mareike Staudt
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074 Aachen, Germany
| | - Sakine Simsekyilmaz
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074 Aachen, Germany
| | - Isabella Kanzler
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074 Aachen, Germany
| | - Peter Boor
- Institute for Pathology, RWTH Aachen University, 52074 Aachen, Germany
- Division of Nephrology and Clinical Immunology, RWTH Aachen University, 52074 Aachen, Germany
- Institute of Molecular Biomedicine, Comenius University, 811 08 Bratislava, Slovakia
| | | | - Xiaofeng Li
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074 Aachen, Germany
| | - Octavian Bucur
- “Victor Babes” National Institute of Pathology, 050096 Bucharest, Romania
- Viron Molecular Medicine Institute, 1 Boston Place, Ste 2600, Boston, MA 02108, USA
| | - Adnan Kaabi
- Department for Cardiology, Angiology and Internal Intensive Care, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany
| | - Yichen Xu
- Department for Cardiology, Angiology and Internal Intensive Care, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany
- Institute for Molecular Medicine, University of Southern Denmark, 5230 Odense, Denmark
| | - Huabo Zheng
- Department for Cardiology, Angiology and Internal Intensive Care, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany
- Institute for Molecular Medicine, University of Southern Denmark, 5230 Odense, Denmark
| | - Pakhwan Nilcham
- Department for Cardiology, Angiology and Internal Intensive Care, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany
| | - Alexander Schuh
- Department for Cardiology, Angiology and Internal Intensive Care, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany
| | - Mihaela Rusu
- Department for Cardiology, Angiology and Internal Intensive Care, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany
- Correspondence: (M.R.); (E.A.L.); Tel.: +49-241-80-35984 (M.R.); +45-6550-4015 (E.A.L.)
| | - Elisa A. Liehn
- Department for Cardiology, Angiology and Internal Intensive Care, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany
- “Victor Babes” National Institute of Pathology, 050096 Bucharest, Romania
- Institute for Molecular Medicine, University of Southern Denmark, 5230 Odense, Denmark
- National Heart Center Singapore, 5 Hospital Dr., Singapore 169609, Singapore
- Correspondence: (M.R.); (E.A.L.); Tel.: +49-241-80-35984 (M.R.); +45-6550-4015 (E.A.L.)
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Inflammation in myocardial infarction: roles of mesenchymal stem cells and their secretome. Cell Death Dis 2022; 8:452. [DOI: 10.1038/s41420-022-01235-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 09/25/2022] [Accepted: 10/21/2022] [Indexed: 11/11/2022]
Abstract
AbstractInflammation plays crucial roles in the regulation of pathophysiological processes involved in injury, repair and remodeling of the infarcted heart; hence, it has become a promising target to improve the prognosis of myocardial infarction (MI). Mesenchymal stem cells (MSCs) serve as an effective and innovative treatment option for cardiac repair owing to their paracrine effects and immunomodulatory functions. In fact, transplanted MSCs have been shown to accumulate at injury sites of heart, exerting multiple effects including immunomodulation, regulating macrophages polarization, modulating the activation of T cells, NK cells and dendritic cells and alleviating pyroptosis of non-immune cells. Many studies also proved that preconditioning of MSCs can enhance their inflammation-regulatory effects. In this review, we provide an overview on the current understanding of the mechanisms on MSCs and their secretome regulating inflammation and immune cells after myocardial infarction and shed light on the applications of MSCs in the treatment of cardiac infarction.
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Sriranjan R, Zhao TX, Tarkin J, Hubsch A, Helmy J, Vamvaka E, Jalaludeen N, Bond S, Hoole SP, Knott P, Buckenham S, Warnes V, Bird N, Cheow H, Templin H, Cacciottolo P, Rudd JHF, Mallat Z, Cheriyan J. Low-dose interleukin 2 for the reduction of vascular inflammati on in acute corona ry syndromes (IVORY): protocol and study rationale for a randomised, double-blind, placebo-controlled, phase II clinical trial. BMJ Open 2022; 12:e062602. [PMID: 36207050 PMCID: PMC9558794 DOI: 10.1136/bmjopen-2022-062602] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Accepted: 07/19/2022] [Indexed: 01/14/2023] Open
Abstract
INTRODUCTION Inflammation plays a critical role in the pathogenesis of atherosclerosis, the leading cause of ischaemic heart disease (IHD). Studies in preclinical models have demonstrated that an increase in regulatory T cells (Tregs), which have a potent immune modulatory action, led to a regression of atherosclerosis. The Low-dose InterLeukin 2 (IL-2) in patients with stable ischaemic heart disease and Acute Coronary Syndromes (LILACS) study, established the safety of low-dose IL-2 and its biological efficacy in IHD. The IVORY trial is designed to assess the effects of low-dose IL-2 on vascular inflammation in patients with acute coronary syndromes (ACS). METHODS AND ANALYSIS In this study, we hypothesise that low-dose IL-2 will reduce vascular inflammation in patients presenting with ACS. This is a double-blind, randomised, placebo-controlled, phase II clinical trial. Patients will be recruited across two centres, a district general hospital and a tertiary cardiac centre in Cambridge, UK. Sixty patients with ACS (unstable angina, non-ST elevation myocardial infarction or ST elevation myocardial infarction) with high-sensitivity C reactive protein (hsCRP) levels >2 mg/L will be randomised to receive either 1.5×106 IU of low-dose IL-2 or placebo (1:1). Dosing will commence within 14 days of admission. Dosing will comprise of an induction and a maintenance phase. 2-Deoxy-2-[fluorine-18] fluoro-D-glucose (18F-FDG) positron emission tomography/CT (PET/CT) scans will be performed before and after dosing. The primary endpoint is the change in mean maximum target to background ratios (TBRmax) in the index vessel between baseline and follow-up scans. Changes in circulating T-cell subsets will be measured as secondary endpoints of the study. The safety and tolerability of extended dosing with low-dose IL-2 in patients with ACS will be evaluated throughout the study. ETHICS AND DISSEMINATION The Health Research Authority and Health and Care Research Wales, UK (19/YH/0171), approved the study. Written informed consent is required to participate in the trial. The results will be reported through peer-reviewed journals and conference presentations. TRIAL REGISTRATION NUMBER NCT04241601.
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Affiliation(s)
- Rouchelle Sriranjan
- Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK
| | - Tian Xiao Zhao
- Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK
| | - Jason Tarkin
- Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK
| | - Annette Hubsch
- Department of Medicine, Division of Experimental Medicine and Immunotherapeutics (EMIT), University of Cambridge, Cambridge, UK
| | - Joanna Helmy
- Department of Medicine, Division of Experimental Medicine and Immunotherapeutics (EMIT), University of Cambridge, Cambridge, UK
| | - Evangelia Vamvaka
- Department of Medicine, Division of Experimental Medicine and Immunotherapeutics (EMIT), University of Cambridge, Cambridge, UK
| | - Navazh Jalaludeen
- Department of Medicine, Division of Experimental Medicine and Immunotherapeutics (EMIT), University of Cambridge, Cambridge, UK
| | - Simon Bond
- Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Stephen P Hoole
- Cardiology, Papworth Hospital NHS Foundation Trust, Cambridge, UK
| | - Philip Knott
- Department of Clinical Immunology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Samantha Buckenham
- Department of Clinical Immunology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Victoria Warnes
- Department of Nuclear Medicine, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Nick Bird
- Department of Nuclear Medicine, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Heok Cheow
- Department of Nuclear Medicine, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Heike Templin
- Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Paul Cacciottolo
- Department of Medicine, Division of Experimental Medicine and Immunotherapeutics (EMIT), University of Cambridge, Cambridge, UK
| | - James H F Rudd
- Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK
| | - Ziad Mallat
- Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK
| | - Joseph Cheriyan
- Department of Medicine, Division of Experimental Medicine and Immunotherapeutics (EMIT), University of Cambridge, Cambridge, UK
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Kubota A, Frangogiannis NG. Macrophages in myocardial infarction. Am J Physiol Cell Physiol 2022; 323:C1304-C1324. [PMID: 36094436 PMCID: PMC9576166 DOI: 10.1152/ajpcell.00230.2022] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 09/06/2022] [Accepted: 09/06/2022] [Indexed: 11/22/2022]
Abstract
The heart contains a population of resident macrophages that markedly expands following injury through recruitment of monocytes and through proliferation of macrophages. In myocardial infarction, macrophages have been implicated in both injurious and reparative responses. In coronary atherosclerotic lesions, macrophages have been implicated in disease progression and in the pathogenesis of plaque rupture. Following myocardial infarction, resident macrophages contribute to initiation and regulation of the inflammatory response. Phagocytosis and efferocytosis are major functions of macrophages during the inflammatory phase of infarct healing, and mediate phenotypic changes, leading to acquisition of an anti-inflammatory macrophage phenotype. Infarct macrophages respond to changes in the cytokine content and extracellular matrix composition of their environment and secrete fibrogenic and angiogenic mediators, playing a central role in repair of the infarcted heart. Macrophages may also play a role in scar maturation and may contribute to chronic adverse remodeling of noninfarcted segments. Single cell studies have revealed a remarkable heterogeneity of macrophage populations in infarcted hearts; however, the relations between transcriptomic profiles and functional properties remain poorly defined. This review manuscript discusses the fate, mechanisms of expansion and activation, and role of macrophages in the infarcted heart. Considering their critical role in injury, repair, and remodeling, macrophages are important, but challenging, targets for therapeutic interventions in myocardial infarction.
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Affiliation(s)
- Akihiko Kubota
- Department of Medicine (Cardiology), Albert Einstein College of Medicine, The Wilf Family Cardiovascular Research Institute, Bronx, New York
| | - Nikolaos G Frangogiannis
- Department of Medicine (Cardiology), Albert Einstein College of Medicine, The Wilf Family Cardiovascular Research Institute, Bronx, New York
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32
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Fan S, Hu Y, You Y, Xue W, Chai R, Zhang X, Shou X, Shi J. Role of resveratrol in inhibiting pathological cardiac remodeling. Front Pharmacol 2022; 13:924473. [PMID: 36120366 PMCID: PMC9475218 DOI: 10.3389/fphar.2022.924473] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 08/04/2022] [Indexed: 12/05/2022] Open
Abstract
Cardiovascular disease is a group of diseases with high mortality in clinic, including hypertension, coronary heart disease, cardiomyopathy, heart valve disease, heart failure, to name a few. In the development of cardiovascular diseases, pathological cardiac remodeling is the most common cardiac pathological change, which often becomes a domino to accelerate the deterioration of the disease. Therefore, inhibiting pathological cardiac remodeling may delay the occurrence and development of cardiovascular diseases and provide patients with greater long-term benefits. Resveratrol is a non-flavonoid polyphenol compound. It mainly exists in grapes, berries, peanuts and red wine, and has cardiovascular protective effects, such as anti-oxidation, inhibiting inflammatory reaction, antithrombotic, dilating blood vessels, inhibiting apoptosis and delaying atherosclerosis. At present, the research of resveratrol has made rich progress. This review aims to summarize the possible mechanism of resveratrol against pathological cardiac remodeling, in order to provide some help for the in-depth exploration of the mechanism of inhibiting pathological cardiac remodeling and the development and research of drug targets.
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Affiliation(s)
- Shaowei Fan
- Department of cardiological medicine, China Academy of Chinese Medical Sciences Guang’anmen Hospital, Beijing, China
| | - Yuanhui Hu
- Department of cardiological medicine, China Academy of Chinese Medical Sciences Guang’anmen Hospital, Beijing, China
- *Correspondence: Yuanhui Hu,
| | - Yaping You
- Department of cardiological medicine, China Academy of Chinese Medical Sciences Guang’anmen Hospital, Beijing, China
| | - Wenjing Xue
- Graduate School of Beijing University of Chinese Medicine, Beijing, China
| | - Ruoning Chai
- Department of cardiological medicine, China Academy of Chinese Medical Sciences Guang’anmen Hospital, Beijing, China
| | - Xuesong Zhang
- Department of cardiological medicine, China Academy of Chinese Medical Sciences Guang’anmen Hospital, Beijing, China
| | - Xintian Shou
- Graduate School of Beijing University of Chinese Medicine, Beijing, China
| | - Jingjing Shi
- Department of cardiological medicine, China Academy of Chinese Medical Sciences Guang’anmen Hospital, Beijing, China
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Malko D, Elmzzahi T, Beyer M. Implications of regulatory T cells in non-lymphoid tissue physiology and pathophysiology. Front Immunol 2022; 13:954798. [PMID: 35936011 PMCID: PMC9354719 DOI: 10.3389/fimmu.2022.954798] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 06/29/2022] [Indexed: 11/26/2022] Open
Abstract
Treg cells have been initially described as gatekeepers for the control of autoimmunity, as they can actively suppress the activity of other immune cells. However, their role goes beyond this as Treg cells further control immune responses during infections and tumor development. Furthermore, Treg cells can acquire additional properties for e.g., the control of tissue homeostasis. This is instructed by a specific differentiation program and the acquisition of effector properties unique to Treg cells in non-lymphoid tissues. These tissue Treg cells can further adapt to their tissue environment and acquire distinct functional properties through specific transcription factors activated by a combination of tissue derived factors, including tissue-specific antigens and cytokines. In this review, we will focus on recent findings extending our current understanding of the role and differentiation of these tissue Treg cells. As such we will highlight the importance of tissue Treg cells for tissue maintenance, regeneration, and repair in adipose tissue, muscle, CNS, liver, kidney, reproductive organs, and the lung.
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Affiliation(s)
- Darya Malko
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia
- Immunogenomics and Neurodegeneration, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany
| | - Tarek Elmzzahi
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia
- Immunogenomics and Neurodegeneration, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany
| | - Marc Beyer
- Immunogenomics and Neurodegeneration, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany
- Platform foR SinglE Cell GenomIcS and Epigenomics (PRECISE), Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) and University of Bonn, Bonn, Germany
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Diaz Villamil E, De Roeck L, Vanorlé M, Communi D. UTP Regulates the Cardioprotective Action of Transplanted Stem Cells Derived From Mouse Cardiac Adipose Tissue. Front Pharmacol 2022; 13:906173. [PMID: 35784739 PMCID: PMC9240194 DOI: 10.3389/fphar.2022.906173] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 05/20/2022] [Indexed: 11/26/2022] Open
Abstract
Adipose tissue is a source of stem cells with a high potential of differentiation for cell-based regenerative therapies. We previously identified mouse P2Y2, an ATP and UTP nucleotide receptor, as a regulator of adipogenic and endothelial differentiation of cardiac adipose-derived stem cells (cADSC). We investigated here the potential involvement of P2Y2 receptor in the cardioprotective action of undifferentiated cADSC transplantation in mouse ischemic heart. Transplantation of cADSC was realized in the periphery of the infarcted zone of ischemic heart, 3 days after left anterior descending artery ligation. A strong reduction of collagen stained area was observed 14 days after cADSC injection, compared to PBS injection. Interestingly, loss of P2Y2 expression totally inhibits the ability of transplanted cADSC to reduce cardiac fibrosis. A detailed gene ontology enrichment analysis was realized by comparing RNA-sequencing data obtained for UTP-treated wild type cASDC and UTP-treated P2Y2-null cASDC. We identified UTP target genes linked to extracellular matrix organization such as matrix metalloproteinases and various collagen types, UTP target genes related to macrophage chemotaxis and differentiation into pro-fibrotic foam cells, and a significant number of UTP target genes linked to angiogenesis regulation. More particularly, we showed that UTP regulated the secretion of CCL5, CXCL5, and CCL12 chemokines and serum amyloid apolipoprotein 3, in the supernatants of UTP-treated cADSC. Interestingly, CCL5 is reported as a key factor in post-infarction heart failure and in the reparative and angiogenic action of transplanted ADSC on ischemic tissue. We investigated then if a UTP-pretreatment of cADSC amplifies their effect on cardiac revascularization in mouse ischemic heart. Transplantation of cADSC was able to increase peri-infarct capillary density, 14 days after their injection. This beneficial effect on cardiac revascularization was enhanced by a UTP-pretreatment of cADSC before their transplantation, and not observed using P2Y2-null cADSC. Our data support that the efficacy of transplanted cADSC can be regulated by the release of inflammatory mediators such as extracellular nucleotides in the ischemic site. The present study highlights the P2Y2 receptor as a regulator of cADSC cardioprotective action, and as a potential target for the therapeutic use of undifferentiated cADSC in post-ischemic cardiac ischemia.
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Affiliation(s)
| | | | | | - Didier Communi
- *Correspondence: Didier Communi, , orcid.org/0000-0003-1050-1493
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Liu J, Liang X, Li M, Lin F, Ma X, Xin Y, Meng Q, Zhuang R, Zhang Q, Han W, Gao L, He Z, Zhou X, Liu Z. Intramyocardial injected human umbilical cord-derived mesenchymal stem cells (HucMSCs) contribute to the recovery of cardiac function and the migration of CD4 + T cells into the infarcted heart via CCL5/CCR5 signaling. Stem Cell Res Ther 2022; 13:247. [PMID: 35690805 PMCID: PMC9188247 DOI: 10.1186/s13287-022-02914-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 05/25/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Human umbilical cord-derived mesenchymal stem cells (HucMSCs) have been recognized as a promising cell for treating myocardial infarction (MI). Inflammatory response post MI is critical in determining the cardiac function and subsequent adverse left ventricular remodeling. However, the local inflammatory effect of HucMSCs after intramyocardial injection in murine remains unclear. METHODS HucMSCs were cultured and transplanted into the mice after MI surgery. Cardiac function of mice were analyzed among MI-N.S, MI-HucMSC and MI-HucMSC-C-C Motif Chemokine receptor 5 (CCR5) antagonist groups, and angiogenesis, fibrosis and hypertrophy, and immune cells infiltration of murine hearts were evaluated between MI-N.S and MI-HucMSC groups. We detected the expression of inflammatory cytokines and their effects on CD4+ T cells migration. RESULTS HucMSCs treatment can significantly improve the cardiac function and some cells can survive at least 28 days after MI. Intramyocardial administration of HucMSCs also improved angiogenesis and alleviated cardiac fibrosis and hypertrophy. Moreover, we found the much higher numbers of CD4+ T cells and CD4+FoxP3+ regulatory T cells (Tregs) in the heart with HucMSCs than that with N.S treatment on day 7 post MI. In addition, the protein level of C-C Motif Chemokine Ligand 5 (CCL5) greatly increased in HucMSCs treated heart compared to MI-N.S group. In vitro, HucMSCs inhibited CD4+ T cells migration and addition of CCL5 antibody or CCR5 antagonist significantly reversed this effect. In vivo results further showed that addition of CCR5 antagonist can reduce the cardioprotective effect of HucMSCs administration on day 7 post MI injury. CONCLUSION These findings indicated that HucMSCs contributed to cardiac functional recovery and attenuated cardiac remodeling post MI. Intramyocardial injection of HucMSCs upregulated the CD4+FoxP3+ Tregs and contributed to the migration of CD4+ T cells into the injured heart via CCL5/CCR5 pathway.
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Affiliation(s)
- Jing Liu
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong, Shanghai, 200120, People's Republic of China
- Department of Burn and Plastic Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, People's Republic of China
| | - Xiaoting Liang
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong, Shanghai, 200120, People's Republic of China
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200120, People's Republic of China
| | - Mimi Li
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong, Shanghai, 200120, People's Republic of China
- Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, People's Republic of China
| | - Fang Lin
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong, Shanghai, 200120, People's Republic of China
- Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, People's Republic of China
| | - Xiaoxue Ma
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong, Shanghai, 200120, People's Republic of China
- Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, People's Republic of China
| | - Yuanfeng Xin
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong, Shanghai, 200120, People's Republic of China
- Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong, Shanghai, 200120, People's Republic of China
| | - Qingshu Meng
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong, Shanghai, 200120, People's Republic of China
- Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, People's Republic of China
| | - Rulin Zhuang
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong, Shanghai, 200120, People's Republic of China
- Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong, Shanghai, 200120, People's Republic of China
| | - Qingliu Zhang
- Department of Heart Failure, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, People's Republic of China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, People's Republic of China
| | - Wei Han
- Department of Heart Failure, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, People's Republic of China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, People's Republic of China
| | - Ling Gao
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200123, People's Republic of China
| | - Zhiying He
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200120, People's Republic of China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, People's Republic of China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, 200335, People's Republic of China
| | - Xiaohui Zhou
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong, Shanghai, 200120, People's Republic of China.
- Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, People's Republic of China.
| | - Zhongmin Liu
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong, Shanghai, 200120, People's Republic of China.
- Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, People's Republic of China.
- Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong, Shanghai, 200120, People's Republic of China.
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, People's Republic of China.
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Lu J, Cen Z, Tang Q, Dong J, Qin L, Wu W. The absence of B cells disrupts splenic and myocardial Treg homeostasis in coxsackievirus B3-induced myocarditis. Clin Exp Immunol 2022; 208:1-11. [PMID: 35262174 PMCID: PMC9113299 DOI: 10.1093/cei/uxac015] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 01/27/2022] [Accepted: 02/05/2022] [Indexed: 01/12/2023] Open
Abstract
Although B cells are essential for humoral immunity and show noteworthy immunomodulatory activity through antibody-independent functions, the role of B cells in regulating Treg cell responses remains controversial. Tregs (CD4+CD25+Foxp3+) are considered to play an immunoprotective role in viral myocarditis (VMC) by controlling autoimmune effector T cells. Here, we proved that B-cell knockout can not only lead to significant reductions in Tregs in the spleen, blood, and heart of VMC mice but also decrease the activation and immune function of splenic Tregs, which was reversed by adoptive transfer of B cells; the transcription levels of TGF-β and Foxp3 in the myocardium were also significantly reduced. B-cell depletion by anti-CD20 impaired the anti-inflammatory function of splenic Tregs and the homeostasis of myocardial Tregs population. Moreover, B cells can convert CD4+CD25- T cells into Foxp3+ and Foxp3-, two functionally suppressive Treg subgroups. Although the reduction in myocardial inflammation in BKO mice indicates that B cells may play a proinflammatory role, the beneficial side of B cells cannot be ignored, that is, to control autoimmunity by maintaining Treg numbers. The results observed in the animal model of VMC highlight the potential harm of rituximab in the nonselective depletion of B cells in clinical applications.
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Affiliation(s)
- Jing Lu
- Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Shuangyong Road 6, Nanning, Guangxi Zhuang Autonomous Region 530021, Peoples Republic of China
| | - Zhihong Cen
- Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Shuangyong Road 6, Nanning, Guangxi Zhuang Autonomous Region 530021, Peoples Republic of China
| | - Quan Tang
- Coronary Care Unit, Nanning First People”s Hospital. Qixing Road 89, Nanning, Guangxi Zhuang Autonomous Region 530021, Peoples Republic of China
| | - Jingwei Dong
- Department of nuclear medicine, Liuzhou People’s Hospital, Wenchang Road 8, Liuzhou, Guangxi Zhuang Autonomous Region 530021, Peoples Republic of China
| | - Lin Qin
- Coronary Care Unit, Nanning First People”s Hospital. Qixing Road 89, Nanning, Guangxi Zhuang Autonomous Region 530021, Peoples Republic of China
| | - Weifeng Wu
- Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Shuangyong Road 6, Nanning, Guangxi Zhuang Autonomous Region 530021, Peoples Republic of China
- Key Laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education, Center for Translational Medicine, Guangxi Medical University, Shuangyong Road 22, Nanning, Guangxi Zhuang Autonomous Region 530021, Peoples Republic of China
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Mallat Z, Binder CJ. The why and how of adaptive immune responses in ischemic cardiovascular disease. NATURE CARDIOVASCULAR RESEARCH 2022; 1:431-444. [PMID: 36382200 PMCID: PMC7613798 DOI: 10.1038/s44161-022-00049-1] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 03/10/2022] [Indexed: 02/02/2023]
Abstract
Atherosclerotic cardiovascular disease is a major cause of disability and death worldwide. Most therapeutic approaches target traditional risk factors but ignore the fundamental role of the immune system. This is a huge unmet need. Recent evidence indicates that reducing inflammation may limit cardiovascular events. However, the concomitant increase in the risk of lifethreatening infections is a major drawback. In this context, targeting adaptive immunity could constitute a highly effective and safer approach. In this Review, we address the why and how of the immuno-cardiovascular unit, in health and in atherosclerotic disease. We review and discuss fundamental mechanisms that ensure immune tolerance to cardiovascular tissue, and examine how their disruption promotes disease progression. We identify promising strategies to manipulate the adaptive immune system for patient benefit, including novel biologics and RNA-based vaccination strategies. Finally, we advocate for establishing a molecular classification of atherosclerosis as an important milestone in our quest to radically change the understanding and treatment of atherosclerotic disease.
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Affiliation(s)
- Ziad Mallat
- Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, Cambridge, UK
- Unversité de Paris, and INSERM U970, Paris Cardiovascular Research Centre, Paris, France
| | - Christoph J. Binder
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
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Properties and Functions of Fibroblasts and Myofibroblasts in Myocardial Infarction. Cells 2022; 11:cells11091386. [PMID: 35563692 PMCID: PMC9102016 DOI: 10.3390/cells11091386] [Citation(s) in RCA: 116] [Impact Index Per Article: 38.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 04/12/2022] [Accepted: 04/16/2022] [Indexed: 12/14/2022] Open
Abstract
The adult mammalian heart contains abundant interstitial and perivascular fibroblasts that expand following injury and play a reparative role but also contribute to maladaptive fibrotic remodeling. Following myocardial infarction, cardiac fibroblasts undergo dynamic phenotypic transitions, contributing to the regulation of inflammatory, reparative, and angiogenic responses. This review manuscript discusses the mechanisms of regulation, roles and fate of fibroblasts in the infarcted heart. During the inflammatory phase of infarct healing, the release of alarmins by necrotic cells promotes a pro-inflammatory and matrix-degrading fibroblast phenotype that may contribute to leukocyte recruitment. The clearance of dead cells and matrix debris from the infarct stimulates anti-inflammatory pathways and activates transforming growth factor (TGF)-β cascades, resulting in the conversion of fibroblasts to α-smooth muscle actin (α-SMA)-expressing myofibroblasts. Activated myofibroblasts secrete large amounts of matrix proteins and form a collagen-based scar that protects the infarcted ventricle from catastrophic complications, such as cardiac rupture. Moreover, infarct fibroblasts may also contribute to cardiac repair by stimulating angiogenesis. During scar maturation, fibroblasts disassemble α-SMA+ stress fibers and convert to specialized cells that may serve in scar maintenance. The prolonged activation of fibroblasts and myofibroblasts in the infarct border zone and in the remote remodeling myocardium may contribute to adverse remodeling and to the pathogenesis of heart failure. In addition to their phenotypic plasticity, fibroblasts exhibit remarkable heterogeneity. Subsets with distinct phenotypic profiles may be responsible for the wide range of functions of fibroblast populations in infarcted and remodeling hearts.
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Teh YC, Chooi MY, Liu D, Kwok I, Lai GC, Ayub Ow Yong L, Ng M, Li JLY, Tan Y, Evrard M, Tan L, Liong KH, Leong K, Goh CC, Chan AYJ, Shadan NB, Mantri CK, Hwang YY, Cheng H, Cheng T, Yu W, Tey HL, Larbi A, St John A, Angeli V, Ruedl C, Lee B, Ginhoux F, Chen SL, Ng LG, Ding JL, Chong SZ. Transitional premonocytes emerge in the periphery for host defense against bacterial infections. SCIENCE ADVANCES 2022; 8:eabj4641. [PMID: 35245124 PMCID: PMC8896792 DOI: 10.1126/sciadv.abj4641] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/17/2023]
Abstract
Circulating Ly6Chi monocytes often undergo cellular death upon exhaustion of their antibacterial effector functions, which limits their capacity for subsequent macrophage differentiation. This shrouds the understanding on how the host replaces the tissue-resident macrophage niche effectively during bacterial invasion to avert infection morbidity. Here, we show that proliferating transitional premonocytes (TpMos), an immediate precursor of mature Ly6Chi monocytes (MatMos), were mobilized into the periphery in response to acute bacterial infection and sepsis. TpMos were less susceptible to apoptosis and served as the main source of macrophage replenishment when MatMos were vulnerable toward bacteria-induced cellular death. Furthermore, TpMo and its derived macrophages contributed to host defense by balancing the proinflammatory cytokine response of MatMos. Consequently, adoptive transfer of TpMos improved the survival outcome of lethal sepsis. Our findings hence highlight a protective role for TpMos during bacterial infections and their contribution toward monocyte-derived macrophage heterogeneity in distinct disease outcomes.
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Affiliation(s)
- Ye Chean Teh
- Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore 138648, Singapore
- Department of Biological Science, National University of Singapore (NUS), Singapore 117543, Singapore
| | - Ming Yao Chooi
- Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore 138648, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Singapore
| | - Dehua Liu
- Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore 138648, Singapore
| | - Immanuel Kwok
- Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore 138648, Singapore
| | - Ghee Chuan Lai
- Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore 138648, Singapore
| | - Liyana Ayub Ow Yong
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Singapore
- Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore 138672, Singapore
| | - Melissa Ng
- Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore 138648, Singapore
| | - Jackson L. Y. Li
- Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore 138648, Singapore
| | - Yingrou Tan
- Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore 138648, Singapore
- National Skin Centre, 1 Mandalay Road, Singapore 308205, Singapore
| | - Maximilien Evrard
- Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore 138648, Singapore
| | - Leonard Tan
- Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore 138648, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Singapore
| | - Ka Hang Liong
- Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore 138648, Singapore
| | - Keith Leong
- Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore 138648, Singapore
| | - Chi Ching Goh
- Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore 138648, Singapore
| | - Andrew Y. J. Chan
- Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore 138648, Singapore
| | - Nurhidaya Binte Shadan
- Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore 138648, Singapore
| | - Chinmay Kumar Mantri
- Program in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore 169857, Singapore
| | - You Yi Hwang
- Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore 138648, Singapore
| | - Hui Cheng
- State Key Laboratory of Experimental Hematology, National Clinical Research Centre for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
| | - Tao Cheng
- State Key Laboratory of Experimental Hematology, National Clinical Research Centre for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
| | - Weimiao Yu
- Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore 138673, Singapore
| | - Hong Liang Tey
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Singapore
- National Skin Centre, 1 Mandalay Road, Singapore 308205, Singapore
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore
| | - Anis Larbi
- Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore 138648, Singapore
| | - Ashley St John
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Singapore
- Program in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore 169857, Singapore
| | - Veronique Angeli
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Singapore
| | - Christiane Ruedl
- School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore
| | - Bernett Lee
- Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore 138648, Singapore
| | - Florent Ginhoux
- Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore 138648, Singapore
- Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China
| | - Swaine L. Chen
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Singapore
- Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore 138672, Singapore
| | - Lai Guan Ng
- Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore 138648, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Singapore
- State Key Laboratory of Experimental Hematology, National Clinical Research Centre for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
- School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore
- Corresponding author. (L.G.N.); (J.L.D.); (S.Z.C.)
| | - Jeak Ling Ding
- Department of Biological Science, National University of Singapore (NUS), Singapore 117543, Singapore
- Corresponding author. (L.G.N.); (J.L.D.); (S.Z.C.)
| | - Shu Zhen Chong
- Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore 138648, Singapore
- Corresponding author. (L.G.N.); (J.L.D.); (S.Z.C.)
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Peterson EA, Sun J, Wang J. Leukocyte-Mediated Cardiac Repair after Myocardial Infarction in Non-Regenerative vs. Regenerative Systems. J Cardiovasc Dev Dis 2022; 9:63. [PMID: 35200716 PMCID: PMC8877434 DOI: 10.3390/jcdd9020063] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 02/17/2022] [Accepted: 02/18/2022] [Indexed: 02/01/2023] Open
Abstract
Innate and adaptive leukocytes rapidly mobilize to ischemic tissues after myocardial infarction in response to damage signals released from necrotic cells. Leukocytes play important roles in cardiac repair and regeneration such as inflammation initiation and resolution; the removal of dead cells and debris; the deposition of the extracellular matrix and granulation tissue; supporting angiogenesis and cardiomyocyte proliferation; and fibrotic scar generation and resolution. By organizing and comparing the present knowledge of leukocyte recruitment and function after cardiac injury in non-regenerative to regenerative systems, we propose that the leukocyte response to cardiac injury differs in non-regenerative adult mammals such as humans and mice in comparison to cardiac regenerative models such as neonatal mice and adult zebrafish. Specifically, extensive neutrophil, macrophage, and T-cell persistence contributes to a lengthy inflammatory period in non-regenerative systems for adverse cardiac remodeling and heart failure development, whereas their quick removal supports inflammation resolution in regenerative systems for new contractile tissue formation and coronary revascularization. Surprisingly, other leukocytes have not been examined in regenerative model systems. With this review, we aim to encourage the development of improved immune cell markers and tools in cardiac regenerative models for the identification of new immune targets in non-regenerative systems to develop new therapies.
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Affiliation(s)
| | | | - Jinhu Wang
- Division of Cardiology, School of Medicine, Emory University, Atlanta, GA 30322, USA; (E.A.P.); (J.S.)
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Yin X, Wang X, Wang S, Xia Y, Chen H, Yin L, Hu K. Screening for Regulatory Network of miRNA–Inflammation, Oxidative Stress and Prognosis-Related mRNA in Acute Myocardial Infarction: An in silico and Validation Study. Int J Gen Med 2022; 15:1715-1731. [PMID: 35210840 PMCID: PMC8863347 DOI: 10.2147/ijgm.s354359] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 01/24/2022] [Indexed: 12/14/2022] Open
Abstract
Background Acute myocardial infarction (AMI), which commonly leads to heart failure, is among the leading causes of mortality worldwide. The aim of this study was to find potential regulatory network for miRNA-inflammation, oxidative stress and prognosis-related mRNA to uncover molecular mechanisms of AMI. Methods The expression profiles of miRNA and mRNA in the blood samples from AMI patients were downloaded from the Gene Expression Omnibus (GEO) dataset for differential expression analysis. Weighted gene co-expression network analysis (WGCNA) was used to further identify important mRNAs. The negatively regulatory network construction of miRNA–inflammation, oxidative stress and prognosis-related mRNAs was performed, followed by protein–protein interaction (PPI) and functional analysis of mRNAs. Results A total of three pairs of negatively regulatory network of miRNA–inflammation and prognosis-related mRNAs (hsa-miR-636/hsa-miR-491-3p/hsa-miR-188-5p/hsa-miR-188-3p-AQP9, hsa-miR-518a-3p-C5AR1 and hsa-miR-509-3-5p/hsa-miR-127-5p-PLAUR), two pairs of negatively regulatory network of miRNA–oxidative stress and prognosis-related mRNAs (hsa-miR-604-TLR4 and hsa-miR-139-5p-CXCL1) and three pairs of negatively regulatory network of miRNA-inflammation, oxidative stress and prognosis-related mRNA (hsa-miR-634/hsa-miR-591-TLR2, hsa-miR-938-NFKBIA and hsa-miR-520h/hsa-miR-450b-3p-ADM) were identified. In the KEGG analysis, some signaling pathways were identified, such as complement and coagulation cascades, pathogenic Escherichia coli infection, chemokine signaling pathway and cytokine–cytokine receptor interaction and Toll-like receptor signaling pathway. Conclusion Identified negatively regulatory network of miRNA-inflammation/oxidative stress and prognosis-related mRNA may be involved in the process of AMI. Those inflammation/oxidative stress and prognosis-related mRNAs may be diagnostic and prognostic biomarkers for AMI.
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Affiliation(s)
- Xunli Yin
- Department of Cardiovascular Medicine, The Seventh People’s Hospital of Jinan, Jinan, 250100, People’s Republic of China
| | - Xuebing Wang
- Department of Cardiovascular Medicine, The Seventh People’s Hospital of Jinan, Jinan, 250100, People’s Republic of China
| | - Shiai Wang
- Department of Cardiovascular Medicine, The Seventh People’s Hospital of Jinan, Jinan, 250100, People’s Republic of China
| | - Youwei Xia
- Department of Critical Care Medicine, The Seventh People’s Hospital of Jinan, Jinan, 250100, People’s Republic of China
| | - Huihui Chen
- Department of Cardiovascular Medicine, The Seventh People’s Hospital of Jinan, Jinan, 250100, People’s Republic of China
| | - Ling Yin
- Department of Conduit Room, The Seventh People’s Hospital of Jinan, Jinan, 250100, People’s Republic of China
| | - Keqing Hu
- Cardiovascular Department, Central Hospital Affiliated to Shandong First Medical University, Jinan, 250013, People's Republic of China
- Correspondence: Keqing Hu, Central Hospital Affiliated to Shandong First Medical University, Cardiovascular Department,105#, Jiefang Road, Jinan 250013, Shandong, China, Tel +86 0531-85695114, Fax +86 0531-86942457 Email
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Jasinska AJ, Pandrea I, Apetrei C. CCR5 as a Coreceptor for Human Immunodeficiency Virus and Simian Immunodeficiency Viruses: A Prototypic Love-Hate Affair. Front Immunol 2022; 13:835994. [PMID: 35154162 PMCID: PMC8829453 DOI: 10.3389/fimmu.2022.835994] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 01/10/2022] [Indexed: 12/14/2022] Open
Abstract
CCR5, a chemokine receptor central for orchestrating lymphocyte/cell migration to the sites of inflammation and to the immunosurveillance, is involved in the pathogenesis of a wide spectrum of health conditions, including inflammatory diseases, viral infections, cancers and autoimmune diseases. CCR5 is also the primary coreceptor for the human immunodeficiency viruses (HIVs), supporting its entry into CD4+ T lymphocytes upon transmission and in the early stages of infection in humans. A natural loss-of-function mutation CCR5-Δ32, preventing the mutated protein expression on the cell surface, renders homozygous carriers of the null allele resistant to HIV-1 infection. This phenomenon was leveraged in the development of therapies and cure strategies for AIDS. Meanwhile, over 40 African nonhuman primate species are long-term hosts of simian immunodeficiency virus (SIV), an ancestral family of viruses that give rise to the pandemic CCR5 (R5)-tropic HIV-1. Many natural hosts typically do not progress to immunodeficiency upon the SIV infection. They have developed various strategies to minimize the SIV-related pathogenesis and disease progression, including an array of mechanisms employing modulation of the CCR5 receptor activity: (i) deletion mutations abrogating the CCR5 surface expression and conferring resistance to infection in null homozygotes; (ii) downregulation of CCR5 expression on CD4+ T cells, particularly memory cells and cells at the mucosal sites, preventing SIV from infecting and killing cells important for the maintenance of immune homeostasis, (iii) delayed onset of CCR5 expression on the CD4+ T cells during ontogenetic development that protects the offspring from vertical transmission of the virus. These host adaptations, aimed at lowering the availability of target CCR5+ CD4+ T cells through CCR5 downregulation, were countered by SIV, which evolved to alter the entry coreceptor usage toward infecting different CD4+ T-cell subpopulations that support viral replication yet without disruption of host immune homeostasis. These natural strategies against SIV/HIV-1 infection, involving control of CCR5 function, inspired therapeutic approaches against HIV-1 disease, employing CCR5 coreceptor blocking as well as gene editing and silencing of CCR5. Given the pleiotropic role of CCR5 in health beyond immune disease, the precision as well as costs and benefits of such interventions needs to be carefully considered.
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Affiliation(s)
- Anna J. Jasinska
- Division of Infectious Diseases, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
- Department of Molecular Genetics, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland
- Eye on Primates, Los Angeles, CA, United States
| | - Ivona Pandrea
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
- Department of Infectious Diseases and Immunology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States
| | - Cristian Apetrei
- Division of Infectious Diseases, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
- Department of Infectious Diseases and Immunology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States
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Foglio E, Pellegrini L, Russo MA, Limana F. HMGB1-Mediated Activation of the Inflammatory-Reparative Response Following Myocardial Infarction. Cells 2022; 11:cells11020216. [PMID: 35053332 PMCID: PMC8773872 DOI: 10.3390/cells11020216] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 01/04/2022] [Accepted: 01/08/2022] [Indexed: 02/06/2023] Open
Abstract
Different cell types belonging to the innate and adaptive immune system play mutually non-exclusive roles during the different phases of the inflammatory-reparative response that occurs following myocardial infarction. A timely and finely regulation of their action is fundamental for the process to properly proceed. The high-mobility group box 1 (HMGB1), a highly conserved nuclear protein that in the extracellular space can act as a damage-associated molecular pattern (DAMP) involved in a large variety of different processes, such as inflammation, migration, invasion, proliferation, differentiation, and tissue regeneration, has recently emerged as a possible regulator of the activity of different immune cell types in the distinct phases of the inflammatory reparative process. Moreover, by activating endogenous stem cells, inducing endothelial cells, and by modulating cardiac fibroblast activity, HMGB1 could represent a master regulator of the inflammatory and reparative responses following MI. In this review, we will provide an overview of cellular effectors involved in these processes and how HMGB1 intervenes in regulating each of them. Moreover, we will summarize HMGB1 roles in regulating other cell types that are involved in the different phases of the inflammatory-reparative response, discussing how its redox status could affect its activity.
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Affiliation(s)
- Eleonora Foglio
- Technoscience, Parco Scientifico e Tecnologico Pontino, 04100 Latina, Italy;
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy;
| | - Laura Pellegrini
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy;
| | - Matteo Antonio Russo
- IRCCS San Raffaele Roma and MEBIC Consortium, 00166 Rome, Italy;
- San Raffaele University of Rome, 00166 Rome, Italy
| | - Federica Limana
- San Raffaele University of Rome, 00166 Rome, Italy
- Laboratory of Cellular and Molecular Pathology, IRCCS San Raffaele Roma, 00166 Rome, Italy
- Correspondence:
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Vinciguerra M, Romiti S, Wretschko E, D'Abramo M, Rose D, Miraldi F, Greco E. Mitral Plasticity: The Way to Prevent the Burden of Ischemic Mitral Regurgitation? Front Cardiovasc Med 2022; 8:794574. [PMID: 35059449 PMCID: PMC8764438 DOI: 10.3389/fcvm.2021.794574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 12/07/2021] [Indexed: 11/16/2022] Open
Abstract
The ischemic impairment of the left ventricular contractility, followed by an adverse remodeling leading to the displacement of the papillary muscles (PMs), increased tethering forces and loss of valve competence has been the long-term accepted definition of ischemic mitral regurgitation (IMR). Over the years, different approaches of management have attempted to address valve regurgitation, nevertheless failing to achieve satisfactory outcomes. Recent studies have observed some structural and molecular changes of the mitral valve (MV), challenging the concept of a bystander passive to the subvalvular involvement. Indeed, the solely mechanical stretch of the PMs, as in the dilated left ventricle because of the aortic valve regurgitation, is not enough in causing relevant MV regurgitation. This setting triggers a series of structural changes called “mitral plasticity,” leaflets increase in their size among others, ensuring an adequate systolic area closure. In contrast, the ischemic injury not only triggers the mechanical stretch on the subvalvular apparatus but is also a powerful promotor of profibrotic processes, with an upregulation of the transforming growth factor (TGF)-β signaling pathway, leading to a MV with exuberant leaflet thickness and impaired mobility. In this article, we revise the concept of IMR, particularly focusing on the new evidence that supports dynamic changes in the MV apparatus, discussing the consequent clinical insights of “mitral plasticity” and the potential therapeutic implications.
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Affiliation(s)
- Mattia Vinciguerra
- Department of Clinical, Internal Medicine, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
- *Correspondence: Mattia Vinciguerra
| | - Silvia Romiti
- Department of Clinical, Internal Medicine, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Eleonora Wretschko
- Department of Clinical, Internal Medicine, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Mizar D'Abramo
- Department of Clinical, Internal Medicine, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - David Rose
- Lancashire Cardiac Centre, Blackpool Victoria Hospital, Blackpool, United Kingdom
| | - Fabio Miraldi
- Department of Clinical, Internal Medicine, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Ernesto Greco
- Department of Clinical, Internal Medicine, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
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Edlinger C, Paar V, Kheder SH, Krizanic F, Lalou E, Boxhammer E, Butter C, Dworok V, Bannehr M, Hoppe UC, Kopp K, Lichtenauer M. Endothelialization and Inflammatory Reactions After Intracardiac Device Implantation. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1401:1-22. [DOI: 10.1007/5584_2022_712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Hsu Y, Huang K, Cheng K. Resuscitating the Field of Cardiac Regeneration: Seeking Answers from Basic Biology. Adv Biol (Weinh) 2021; 6:e2101133. [PMID: 34939372 DOI: 10.1002/adbi.202101133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 12/02/2021] [Indexed: 11/09/2022]
Abstract
Heart failure (HF) is one of the leading causes for hospital admissions worldwide. HF patients are classified based on the chronic changes in left ventricular ejection fraction (LVEF) as preserved (LVEF ≥ 50%), reduced (LVEF ≤ 40%), or mid-ranged (40% < LVEF < 50%) HFs. Treatments nowadays can prevent HFrEF progress, whereas only a few of the treatments have been proven to be effective in improving the survival of HFpEF. In this review, numerous mediators involved in the pathogenesis of HF are summarized. The regional upstream signaling and their diagnostic and therapeutic potential are also discussed. Additionally, the recent challenges and development in cardiac regenerative therapy that hold opportunities for future research and clinical translation are discussed.
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Affiliation(s)
- Yaching Hsu
- Department of Molecular Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, NC, 27607, USA.,Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill & North Carolina State University, Raleigh, NC, 27607, USA
| | - Ke Huang
- Department of Molecular Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, NC, 27607, USA.,Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill & North Carolina State University, Raleigh, NC, 27607, USA
| | - Ke Cheng
- Department of Molecular Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, NC, 27607, USA.,Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill & North Carolina State University, Raleigh, NC, 27607, USA
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Corker A, Neff LS, Broughton P, Bradshaw AD, DeLeon-Pennell KY. Organized Chaos: Deciphering Immune Cell Heterogeneity's Role in Inflammation in the Heart. Biomolecules 2021; 12:11. [PMID: 35053159 PMCID: PMC8773626 DOI: 10.3390/biom12010011] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 12/10/2021] [Accepted: 12/18/2021] [Indexed: 12/24/2022] Open
Abstract
During homeostasis, immune cells perform daily housekeeping functions to maintain heart health by acting as sentinels for tissue damage and foreign particles. Resident immune cells compose 5% of the cellular population in healthy human ventricular tissue. In response to injury, there is an increase in inflammation within the heart due to the influx of immune cells. Some of the most common immune cells recruited to the heart are macrophages, dendritic cells, neutrophils, and T-cells. In this review, we will discuss what is known about cardiac immune cell heterogeneity during homeostasis, how these cell populations change in response to a pathology such as myocardial infarction or pressure overload, and what stimuli are regulating these processes. In addition, we will summarize technologies used to evaluate cell heterogeneity in models of cardiovascular disease.
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Affiliation(s)
- Alexa Corker
- Department of Medicine, Division of Cardiology, Medical University of South Carolina, Charleston, SC 29425, USA; (A.C.); (L.S.N.); (P.B.); (A.D.B.)
| | - Lily S. Neff
- Department of Medicine, Division of Cardiology, Medical University of South Carolina, Charleston, SC 29425, USA; (A.C.); (L.S.N.); (P.B.); (A.D.B.)
| | - Philip Broughton
- Department of Medicine, Division of Cardiology, Medical University of South Carolina, Charleston, SC 29425, USA; (A.C.); (L.S.N.); (P.B.); (A.D.B.)
| | - Amy D. Bradshaw
- Department of Medicine, Division of Cardiology, Medical University of South Carolina, Charleston, SC 29425, USA; (A.C.); (L.S.N.); (P.B.); (A.D.B.)
- Ralph H. Johnson Veterans Affairs Medical Center, Medical University of South Carolina, Charleston, SC 29401, USA
| | - Kristine Y. DeLeon-Pennell
- Department of Medicine, Division of Cardiology, Medical University of South Carolina, Charleston, SC 29425, USA; (A.C.); (L.S.N.); (P.B.); (A.D.B.)
- Ralph H. Johnson Veterans Affairs Medical Center, Medical University of South Carolina, Charleston, SC 29401, USA
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Kilci H, Altınbilek E, Çetinkal G, Sığırcı S, Koçaş BB, Yıldız SS, Kılıçkesmez KO. Relation of a novel fibrosis marker and post-myocardial infarction left ventricular ejection fraction in revascularized patients. Biomark Med 2021; 15:1651-1658. [PMID: 34704823 DOI: 10.2217/bmm-2021-0003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: To investigate the relationship between post-myocardial infarction (MI) left ventricular ejection fraction (LVEF) and fibrosis marker HE-4 in primarily revascularized patients with ST-segment elevation MI (STEMI). Patients & methods: In 94 consecutive STEMI patients (median age 57 [IQR: 50-69] years; 77.7% male), HE-4 values were measured at hospital admission and 4 days after STEMI. Transthoracic echocardiography was performed 4 days after STEMI (median 5 days [interquartile range: 4-6]). Results: HE-4 levels 4 days after STEMI were significantly higher in the low ejection fraction group (30.1 [26.0-46.5] pmol/l vs 48.5 [32.5-85.9] pmol/l, p = 0.004). In the multivariable analysis, HE-4 values (odds ratio: 1.029, 95% CI: 1.012-1.046, p = 0.001), troponin I levels, anterior MI and diabetes mellitus were independent predictors of low LVEF after STEMI. A negative correlation existed between ΔHE-4 levels and LVEF (r: -0.337, p = 0.001). Receiver operating characteristic analysis indicated 34.01 pmol/l HE-4 at 4 days after STEMI identified patients with low LVEF (AUC = 0.707; 95% CI: 0.601-0.813; p = 0.001). Conclusion: In revascularized STEMI patients, high HE-4 levels are associated with decreased LVEF. HE-4 may represent a diagnostic marker and treatment target for patients with heart failure or left ventricular systolic dysfunction after STEMI.
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Affiliation(s)
- Hakan Kilci
- Department of Cardiology, Sisli Hamidiye Etfal Training & Research Hospital, Istanbul, 34371,Turkey
| | - Ertuğrul Altınbilek
- Department of Emergency, Sisli Hamidiye Etfal Training & Research Hospital, Istanbul, 34371, Turkey
| | - Gökhan Çetinkal
- Department of Cardiology, Sisli Hamidiye Etfal Training & Research Hospital, Istanbul, 34371,Turkey
| | - Serhat Sığırcı
- Department of Cardiology, Sisli Hamidiye Etfal Training & Research Hospital, Istanbul, 34371,Turkey
| | - Betül B Koçaş
- Department of Cardiology, Sisli Hamidiye Etfal Training & Research Hospital, Istanbul, 34371,Turkey
| | - Süleyman S Yıldız
- Department of Cardiology, Sisli Hamidiye Etfal Training & Research Hospital, Istanbul, 34371,Turkey
| | - Kadriye Orta Kılıçkesmez
- Department of Cardiology, Sisli Hamidiye Etfal Training & Research Hospital, Istanbul, 34371,Turkey
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Schumacher D, Liehn EA, Singh A, Curaj A, Wijnands E, Lira SA, Tacke F, Jankowski J, Biessen EA, van der Vorst EP. CCR6 Deficiency Increases Infarct Size after Murine Acute Myocardial Infarction. Biomedicines 2021; 9:1532. [PMID: 34829761 PMCID: PMC8614800 DOI: 10.3390/biomedicines9111532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 10/15/2021] [Accepted: 10/19/2021] [Indexed: 11/20/2022] Open
Abstract
Ischemia-reperfusion injury after the reopening of an occluded coronary artery is a major cause of cardiac damage and inflammation after acute myocardial infarction. The chemokine axis CCL20-CCR6 is a key player in various inflammatory processes, including atherosclerosis; however, its role in ischemia-reperfusion injury has remained elusive. Therefore, to gain more insight into the role of the CCR6 in acute myocardial infarction, we have studied cardiac injury after transient ligation of the left anterior descending coronary artery followed by reperfusion in Ccr6-/- mice and their respective C57Bl/6 wild-type controls. Surprisingly, Ccr6-/- mice demonstrated significantly reduced cardiac function and increased infarct sizes after ischemia/reperfusion. This coincided with a significant increase in cardiac inflammation, characterized by an accumulation of neutrophils and inflammatory macrophage accumulation. Chimeras with a bone marrow deficiency of CCR6 mirrored this adverse Ccr6-/- phenotype, while cardiac injury was unchanged in chimeras with stromal CCR6 deficiency. This study demonstrates that CCR6-dependent (bone marrow) cells exert a protective role in myocardial infarction and subsequent ischemia-reperfusion injury, supporting the notion that augmenting CCR6-dependent immune mechanisms represents an interesting therapeutic target.
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Affiliation(s)
- David Schumacher
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074 Aachen, Germany; (D.S.); (A.C.); (J.J.); (E.A.L.B.)
- Department of Anesthesiology, University Hospital, RWTH Aachen University, 52074 Aachen, Germany
| | - Elisa A. Liehn
- Department of Intensive Care and Intermediate Care, University Hospital, RWTH Aachen University, 52074 Aachen, Germany;
- Department of Cardiology, Angiology and Intensive Medicine, University Hospital Aachen, 52074 Aachen, Germany
- National Institute for Pathology “Victor Babes”, 050096 Bucharest, Romania
- Institute for Molecular Medicine, University of Southern Denmark, 5230 Odense, Denmark
| | - Anjana Singh
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, 6229 ER Maastricht, The Netherlands; (A.S.); (E.W.)
- Cognizant Technology Solutions, Phase II Hinjawadi, Pune 411 057, Maharashtra, India
| | - Adelina Curaj
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074 Aachen, Germany; (D.S.); (A.C.); (J.J.); (E.A.L.B.)
| | - Erwin Wijnands
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, 6229 ER Maastricht, The Netherlands; (A.S.); (E.W.)
| | - Sergio A. Lira
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
| | - Frank Tacke
- Department of Hepatology and Gastroenterolgy, Campus Virchow-Klinikum and Campus Charité Mitte, Charité–Universitätsmedizin Berlin, 13353 Berlin, Germany;
| | - Joachim Jankowski
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074 Aachen, Germany; (D.S.); (A.C.); (J.J.); (E.A.L.B.)
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, 6229 ER Maastricht, The Netherlands; (A.S.); (E.W.)
| | - Erik A.L. Biessen
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074 Aachen, Germany; (D.S.); (A.C.); (J.J.); (E.A.L.B.)
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, 6229 ER Maastricht, The Netherlands; (A.S.); (E.W.)
| | - Emiel P.C. van der Vorst
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074 Aachen, Germany; (D.S.); (A.C.); (J.J.); (E.A.L.B.)
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, 6229 ER Maastricht, The Netherlands; (A.S.); (E.W.)
- Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University, 52074 Aachen, Germany
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich, 80336 Munich, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, 80336 Munich, Germany
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Gupta S, Adhikary S, Hui SP. Decoding the proregenerative competence of regulatory T cells through complex tissue regeneration in zebrafish. Clin Exp Immunol 2021; 206:346-353. [PMID: 34529822 DOI: 10.1111/cei.13661] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 09/03/2021] [Accepted: 09/07/2021] [Indexed: 12/12/2022] Open
Abstract
Regulatory T cells (Tregs ) are specific subtype of T cells that play a central role in sustaining self-antigen tolerance and restricting inflammatory tissue damage. More recently, additional direct functions of Tregs in mammalian tissue repair have emerged, but the regenerative potential of Tregs in non-mammalian vertebrates has not been explored despite the latter possessing a highly developed adaptive immune system. Why complex organs such as the caudal fin, heart, brain, spinal cord and retina regenerate in certain non-mammalian vertebrates, but not in mammals, is an interesting but unresolved question in the field of regenerative biology. Inflammation has traditionally been thought to be an impediment to regeneration due to the formation of scars. Regenerative decline in higher organisms has been speculated to be the evolutionary advent of adaptive immunity. Recent studies, however, have shown that the innate inflammatory response in non-mammalian organisms is required for organ regeneration. It has also been found that highly advanced adaptive immunity is no longer incompatible with regeneration and for that, Tregs are important. Zebrafish regulatory T cells (zTregs ) migrate rapidly to the injury site in damaged organs, where they facilitate the proliferation of regeneration precursor cells by generating tissue-specific regenerative factors by a process distinct from the canonical anti-inflammatory pathway. We review both reparative and proregenerative roles of Tregs in mammals and zebrafish, respectively, and also give an overview of the forkhead box protein 3 (FoxP3) -dependent immunosuppressive function of Tregs in zebrafish, which makes it a useful model organism for future Treg biology and research.
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Affiliation(s)
- Samudra Gupta
- S. N. Pradhan Centre for Neurosciences, University of Calcutta, Kolkata, India
| | - Satadal Adhikary
- Post Graduate Department of Zoology, ABN Seal College, Cooch Behar, India
| | - Subhra Prakash Hui
- S. N. Pradhan Centre for Neurosciences, University of Calcutta, Kolkata, India
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