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Syed F, Ballew O, Lee CC, Rana J, Krishnan P, Castela A, Weaver SA, Chalasani NS, Thomaidou SF, Demine S, Chang G, Coomans de Brachène A, Alvelos MI, Vazquez EM, Marselli L, Orr K, Felton JL, Liu J, Kaddis JS, Marchetti P, Zaldumbide A, Scheuner D, Eizirik DL, Evans-Molina C. Pharmacological inhibition of tyrosine protein-kinase 2 reduces islet inflammation and delays type 1 diabetes onset in mice. EBioMedicine 2025:105734. [PMID: 40335415 DOI: 10.1016/j.ebiom.2025.105734] [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: 09/17/2024] [Revised: 02/20/2025] [Accepted: 04/14/2025] [Indexed: 05/09/2025] Open
Abstract
BACKGROUND Tyrosine protein-kinase 2 (TYK2) mediates inflammatory signalling through multiple cytokines, including interferon-α (IFNα), interleukin (IL)-12, and IL-23. TYK2 missense mutations protect against type 1 diabetes (T1D), and inhibition of TYK2 shows promise in other autoimmune conditions. METHODS We evaluated the effects of specific TYK2 inhibitors (TYK2is) in pre-clinical models of T1D, including human β cells, cadaveric islets, iPSC-derived islets, and mouse models. FINDINGS In vitro studies showed that TYK2is prevented IFNα-induced β cell HLA class I up-regulation, endoplasmic reticulum stress, and chemokine production. In co-culture studies, pre-treatment of β cells with TYK2i prevented IFNα-induced antigenic peptide presentation and alloreactive and autoreactive T cell degranulation. In vivo administration of BMS-986202 in two mouse models of T1D (RIP-LCMV-GP and NOD mice) reduced systemic and tissue-localised inflammation, prevented β cell death, and delayed T1D onset. Transcriptional phenotyping of pancreatic islets, pancreatic lymph nodes, and spleen highlighted a role for TYK2 inhibition in modulating signalling pathways associated with inflammation, translational control, stress signalling, secretory function, immunity, and diabetes. Additionally, TYK2i treatment changed the composition of innate and adaptive immune cell populations in the blood and disease target tissues. INTERPRETATION These findings indicate that TYK2i has beneficial effects on both the immune and endocrine compartments in models of T1D, thus supporting a path forward for testing TYK2is in human T1D. FUNDING This work was supported by the National Institutes of Health (NIH), Veteran Affairs (VA), Breakthrough T1D, and gifts from the Sigma Beta Sorority, the Ball Brothers Foundation, and the George and Frances Ball Foundation.
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Affiliation(s)
- Farooq Syed
- Indiana University School of Medicine, Indianapolis, IN, USA; Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Pediatrics and the Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Diabetes-Immunology, Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope, Duarte, CA, USA
| | - Olivia Ballew
- Indiana Biosciences Research Institute, Indianapolis, IN, USA
| | - Chih-Chun Lee
- Indiana University School of Medicine, Indianapolis, IN, USA; Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Pediatrics and the Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Jyoti Rana
- Indiana University School of Medicine, Indianapolis, IN, USA; Department of Pediatrics and the Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Preethi Krishnan
- Indiana University School of Medicine, Indianapolis, IN, USA; Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Angela Castela
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium
| | - Staci A Weaver
- Indiana University School of Medicine, Indianapolis, IN, USA; Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Pediatrics and the Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA
| | | | - Sofia F Thomaidou
- Department of Cell and Chemical Biology, Leiden University Medical Center, the Netherlands
| | - Stephane Demine
- Indiana Biosciences Research Institute, Indianapolis, IN, USA
| | - Garrick Chang
- Department of Physics, Indiana University Indianapolis, Indianapolis, IN, USA
| | | | - Maria Ines Alvelos
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium
| | - Eugenia Martin Vazquez
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium
| | - Lorella Marselli
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Kara Orr
- Indiana University School of Medicine, Indianapolis, IN, USA; Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Pediatrics and the Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Jamie L Felton
- Indiana University School of Medicine, Indianapolis, IN, USA; Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Pediatrics and the Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Jing Liu
- Department of Physics and Astronomy, Purdue University, West Lafayette, IN, USA
| | - John S Kaddis
- Department of Diabetes and Cancer Discovery Science, Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope, Duarte, CA, USA
| | - Piero Marchetti
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Arnaud Zaldumbide
- Department of Cell and Chemical Biology, Leiden University Medical Center, the Netherlands
| | | | - Decio L Eizirik
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium.
| | - Carmella Evans-Molina
- Indiana University School of Medicine, Indianapolis, IN, USA; Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Pediatrics and the Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA; Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA.
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Raoufi A, Soleimani Samarkhazan H, Nouri S, Khaksari MN, Abbasi Sourki P, Sargazi Aval O, Baradaran B, Aghaei M. Macrophages in graft-versus-host disease (GVHD): dual roles as therapeutic tools and targets. Clin Exp Med 2025; 25:73. [PMID: 40048037 PMCID: PMC11885342 DOI: 10.1007/s10238-025-01588-0] [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: 12/27/2024] [Accepted: 02/03/2025] [Indexed: 03/09/2025]
Abstract
Graft-versus-host disease remains one of the most formidable barriers to the complete success of hematopoietic stem cell transplantation that has emerged as the curative approach for many hematopoietic malignancies because it affects quality of life and overall survival. Macrophages are among the important members of the immune system, which perform dual roles in GVHD as both therapeutic tools and targets. This review epitomizes the multifunctional role of macrophages in the pathophysiology of both acute and chronic GVHD. Macrophages play an important role in the early phase of GVHD because of their recruitment and infiltration into target organs. Furthermore, they polarize into two functionally different phenotypes, including M1 and M2. In the case of acute GVHD, most macrophages express the M1 phenotype characterized by the production of pro-inflammatory cytokines that contribute to tissue damage. In contrast, in chronic GVHD, macrophages tend toward the M2 phenotype associated with the repair of tissues and fibrosis. A critical balance among these phenotypes is central to the course and severity of GVHD. Further interactions of macrophages with other lymphocytes such as T cells, B cells, and fibroblast further determine the course of GVHD. Macrophage interaction associated with alloreactive T cells promotes inflammation. This is therefore important in inducing injuries of tissues during acute GVHD. Interaction of macrophages, B cell, fibroblast, and CD4+ T cells promotes fibrosis during chronic GVHD and, hence, the subsequent dysfunction of organs. These are some insights, while several challenges remain. First, the impact of the dominant cytokines in GVHD on the polarization of macrophages is incompletely characterized and sometimes controversial. Second, the development of targeted therapies able to modulate macrophage function without systemic side effects remains an area of ongoing investigation. Future directions involve the exploration of macrophage-targeted therapies, including small molecules, antibodies, and nanotechnology, which modulate macrophage behavior and improve patient outcomes. This underlines the fact that a profound understanding of the dual role of macrophages in GVHD is essential for developing new and more effective therapeutic strategies. Targeting macrophages might represent one avenue for decreasing the incidence and severity of GVHD and improving the success and safety of HSCT.
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Affiliation(s)
- Atieh Raoufi
- Department of Immunology, Student Research Committee, School of Medicine, Zanjan University of Medical Science, Zanjan, Iran
| | - Hamed Soleimani Samarkhazan
- Student Research Committee, Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sina Nouri
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran
| | - Mohammad Navid Khaksari
- Department of Hematology and Blood Banking, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Parvaneh Abbasi Sourki
- Department of Hematology, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran
| | - Omolbanin Sargazi Aval
- Department of Hematology, Faculty of Allied Medical Sciences, Zabol University of Medical Sciences, Zabol, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Daneshghah Ave, Tabriz, Iran.
| | - Mojtaba Aghaei
- Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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Meyer SP, Bauer R, Brüne B, Schmid T. The role of type I interferon signaling in myeloid anti-tumor immunity. Front Immunol 2025; 16:1547466. [PMID: 40098954 PMCID: PMC11911529 DOI: 10.3389/fimmu.2025.1547466] [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: 12/18/2024] [Accepted: 02/14/2025] [Indexed: 03/19/2025] Open
Abstract
Tumors often arise in chronically inflamed, and thus immunologically highly active niches. While immune cells are able to recognize and remove transformed cells, tumors eventually escape the control of the immune system by shaping their immediate microenvironment. In this context, macrophages are of major importance, as they initially exert anti-tumor functions before they adopt a tumor-associated phenotype that instead inhibits anti-tumor immune responses and even allows for sustaining a smoldering inflammatory, growth promoting tumor microenvironment (TME). Type I interferons (IFNs) are well established modulators of inflammatory reactions. While they have been shown to directly inhibit tumor growth, there is accumulating evidence that they also play an important role in altering immune cell functions within the TME. In the present review, we focus on the impact of type I IFNs on anti-tumor responses, driven by monocytes and macrophages. Specifically, we will provide an overview of tumor-intrinsic factors, which impinge on IFN-stimulated gene (ISG) expression, like the presence of nucleic acids, metabolites, or hypoxia. We will further summarize the current understanding of the consequences of altered IFN responses on macrophage phenotypes, i.e., differentiation, polarization, and functions. For the latter, we will focus on macrophage-mediated tumor cell killing and phagocytosis, as well as on how macrophages affect their environment by secreting cytokines and directly interacting with immune cells. Finally, we will discuss how type I IFN responses in macrophages might affect and should be considered for current and future tumor therapies.
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Affiliation(s)
- Sofie Patrizia Meyer
- Institute of Biochemistry I, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany
| | - Rebekka Bauer
- Institute of Biochemistry I, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany
| | - Bernhard Brüne
- Institute of Biochemistry I, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany
- Frankfurt Cancer Institute, Goethe University Frankfurt, Frankfurt, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology, Frankfurt, Germany
| | - Tobias Schmid
- Institute of Biochemistry I, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany
- German Cancer Consortium (DKTK), Partner Site Frankfurt, Frankfurt, Germany
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Brancewicz J, Wójcik N, Sarnowska Z, Robak J, Król M. The Multifaceted Role of Macrophages in Biology and Diseases. Int J Mol Sci 2025; 26:2107. [PMID: 40076729 PMCID: PMC11900619 DOI: 10.3390/ijms26052107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Revised: 02/24/2025] [Accepted: 02/25/2025] [Indexed: 03/14/2025] Open
Abstract
Macrophages are highly adaptable immune cells capable of responding dynamically to diverse environmental cues. They are pivotal in maintaining homeostasis, orchestrating immune responses, facilitating tissue repair, and, under certain conditions, contributing to disease pathogenesis. This review delves into the complex biology of macrophages, highlighting their polarization states, roles in autoimmune and inflammatory diseases, involvement in cancer progression, and potential as therapeutic targets. By understanding the context-dependent functional plasticity of macrophages, we can better appreciate their contributions to health and disease, paving the way for innovative therapeutic strategies.
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Affiliation(s)
| | | | | | | | - Magdalena Król
- Center of Cellular Immunotherapies, Warsaw University of Life Sciences, Building 23, Level 0, Laboratory Number 0135, 8 Ciszewskiego St., 02-786 Warsaw, Poland
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Almutairi A, White TD, Stephenson DJ, Stephenson BD, Gai-Tusing Y, Goel P, Phillips DW, Welner RS, Lei X, Hammock BD, Chalfant CE, Ramanadham S. Selective Reduction of Ca2+-Independent Phospholipase A2β (iPLA2β)-Derived Lipid Signaling From Macrophages Mitigates Type 1 Diabetes Development. Diabetes 2024; 73:2022-2033. [PMID: 39283670 PMCID: PMC11579405 DOI: 10.2337/db23-0770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 09/07/2024] [Indexed: 11/22/2024]
Abstract
Type 1 diabetes (T1D) is a consequence of autoimmune destruction of β-cells, and macrophages (MΦs) have a central role in initiating processes that lead to β-cell demise. We reported that Ca2+-independent phospholipase A2β (iPLA2β)-derived lipid (iDL) signaling contributes to β-cell death. Because MΦs express iPLA2β, we assessed its role in T1D development. We find that selective reduction of myeloid-iPLA2β in spontaneously diabetes-prone NOD mice 1) decreases proinflammatory eicosanoid production by MΦs, 2) favors the anti-inflammatory (M2-like) MΦ phenotype, and 3) diminishes activated CD4+ and CD8+ T-cells phenotype in the pancreatic infiltrate, prior to T1D onset. These outcomes are associated with a significant reduction in T1D. Further, inhibition of select proinflammatory lipid signaling pathways reduces M1-like MΦ polarization and adoptive transfer of M2-like MΦs reduces NOD T1D incidence, suggesting a mechanism by which iDLs impact T1D development. These findings identify MΦ-iPLA2β as a critical contributor to T1D development and potential target to counter T1D onset. ARTICLE HIGHLIGHTS
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Affiliation(s)
- Abdulaziz Almutairi
- Department of Cell, Developmental, and Integrative Biology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL
- Comprehensive Diabetes Center, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL
- Department of Basic Science, College of Science and Health Professions, King Saud bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
| | - Tayleur D. White
- Department of Cell, Developmental, and Integrative Biology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL
- Comprehensive Diabetes Center, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL
| | - Daniel J. Stephenson
- Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA
| | - Benjamin D. Stephenson
- Program in Cancer Biology, UVA Comprehensive Cancer Center, University of Virginia School of Medicine, Charlottesville, VA
| | - Ying Gai-Tusing
- Department of Cell, Developmental, and Integrative Biology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL
- Comprehensive Diabetes Center, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL
| | - Paran Goel
- Department of Medicine, Hematology & Oncology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL
| | - Daniel W. Phillips
- Department of Medicine, Hematology & Oncology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL
| | - Robert S. Welner
- Comprehensive Diabetes Center, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL
- Department of Medicine, Hematology & Oncology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL
| | - Xiaoyong Lei
- Department of Cell, Developmental, and Integrative Biology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL
- Comprehensive Diabetes Center, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL
| | - Bruce D. Hammock
- Department of Entomology and Nematology, University of California, Davis, Davis, CA
| | - Charles E. Chalfant
- Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA
- Program in Cancer Biology, UVA Comprehensive Cancer Center, University of Virginia School of Medicine, Charlottesville, VA
- Research Service, Richmond Veterans Administration Medical Center, Richmond, VA
| | - Sasanka Ramanadham
- Department of Cell, Developmental, and Integrative Biology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL
- Comprehensive Diabetes Center, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL
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Lai X, Luo J, Luo Y, Zheng Y, Yang H, Zou F. Targeting the autoreactive CD8 + T-cell receptor in type 1 diabetes: Insights from scRNA-seq for immunotherapy. Pharmacol Res 2024; 209:107433. [PMID: 39343113 DOI: 10.1016/j.phrs.2024.107433] [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: 05/15/2024] [Revised: 09/21/2024] [Accepted: 09/23/2024] [Indexed: 10/01/2024]
Abstract
Type 1 Diabetes (T1D) is an autoimmune disease characterized by the attack and destruction of Pancreatic islet beta cells by T cells. Understanding the role of T-cell receptor (TCR) in the development of T1D is of paramount importance. This study employs single-cell RNA sequencing (scRNA-seq) to delve into the mechanistic actions and potential therapeutic applications of autoreactive stem cell-like CD8 TCR in T1D. By retrieving T-cell data from non-obese diabetic (NOD) mice via the GEO database, it was revealed that CD8+ T cells are the predominant T-cell subset in the pancreatic tissue of T1D mice, along with the identification of T-cell marker genes closely associated with T1D. Moreover, the gene TRAJ23 exhibits a preference for T1D, and its knockout alleviates T1D symptoms and adverse reactions in NOD mice. Additionally, engineered TCR-T cells demonstrate significant cytotoxicity towards β cells in T1D.
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Affiliation(s)
- Xiaoyang Lai
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, PR China
| | - Junming Luo
- Department of Respiratory Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, PR China
| | - Yue Luo
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, PR China
| | - Yijing Zheng
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, PR China
| | - Huan Yang
- Department of Endocrinology, Jiujiang University Affiliated Hospital, Jiujiang, PR China
| | - Fang Zou
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, PR China.
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Ni W, Niu Y, Cao S, Fan C, Fan J, Zhu L, Wang X. Intermittent hypoxia exacerbates anxiety in high-fat diet-induced diabetic mice by inhibiting TREM2-regulated IFNAR1 signaling. J Neuroinflammation 2024; 21:166. [PMID: 38956653 PMCID: PMC11218348 DOI: 10.1186/s12974-024-03160-1] [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: 03/20/2024] [Accepted: 06/24/2024] [Indexed: 07/04/2024] Open
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM) and obstructive sleep apnea (OSA) are mutual risk factors, with both conditions inducing cognitive impairment and anxiety. However, whether OSA exacerbates cognitive impairment and anxiety in patients with T2DM remains unclear. Moreover, TREM2 upregulation has been suggested to play a protective role in attenuating microglia activation and improving synaptic function in T2DM mice. The aim of this study was to explore the regulatory mechanisms of TREM2 and the cognitive and anxiety-like behavioral changes in mice with OSA combined with T2DM. METHODS A T2DM with OSA model was developed by treating mice with a 60% kcal high-fat diet (HFD) combined with intermittent hypoxia (IH). Spatial learning memory capacity and anxiety in mice were investigated. Neuronal damage in the brain was determined by the quantity of synapses density, the number and morphology of brain microglia, and pro-inflammatory factors. For mechanism exploration, an in vitro model of T2DM combined with OSA was generated by co-treating microglia with high glucose (HG) and IH. Regulation of TREM2 on IFNAR1-STAT1 pathway was determined by RNA sequencing and qRT-PCR. RESULTS Our results showed that HFD mice exhibited significant cognitive dysfunction and anxiety-like behavior, accompanied by significant synaptic loss. Furthermore, significant activation of brain microglia and enhanced microglial phagocytosis of synapses were observed. Moreover, IH was found to significantly aggravate anxiety in the HFD mice. The mechanism of HG treatment may potentially involve the promotion of TREM2 upregulation, which in turn attenuates the proinflammatory microglia by inhibiting the IFNAR1-STAT1 pathway. Conversely, a significant reduction in TREM2 in IH-co-treated HFD mice and HG-treated microglia resulted in the further activation of the IFNAR1-STAT1 pathway and consequently increased proinflammatory microglial activation. CONCLUSIONS HFD upregulated the IFNAR1-STAT1 pathway and induced proinflammatory microglia, leading to synaptic damage and causing anxiety and cognitive deficits. The upregulated TREM2 inT2DM mice brain exerted a negative regulation of the IFNAR1-STAT1 pathway. Mice with T2DM combined with OSA exacerbated anxiety via the downregulation of TREM2, causing heightened IFNAR1-STAT1 pathway activation and consequently increasing proinflammatory microglia.
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MESH Headings
- Animals
- Mice
- Diet, High-Fat/adverse effects
- Membrane Glycoproteins/metabolism
- Membrane Glycoproteins/genetics
- Receptors, Immunologic/metabolism
- Receptors, Immunologic/genetics
- Anxiety/etiology
- Anxiety/metabolism
- Signal Transduction/physiology
- Signal Transduction/drug effects
- Hypoxia/metabolism
- Hypoxia/complications
- Male
- Mice, Inbred C57BL
- Diabetes Mellitus, Type 2/complications
- Diabetes Mellitus, Type 2/metabolism
- Diabetes Mellitus, Type 2/psychology
- Receptor, Interferon alpha-beta/metabolism
- Receptor, Interferon alpha-beta/genetics
- Diabetes Mellitus, Experimental/complications
- Diabetes Mellitus, Experimental/metabolism
- Microglia/metabolism
- STAT1 Transcription Factor/metabolism
- Sleep Apnea, Obstructive/complications
- Sleep Apnea, Obstructive/metabolism
- Sleep Apnea, Obstructive/psychology
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Affiliation(s)
- Wenyu Ni
- Qidong People's Hospital, Affiliated Qidong Hospital of Nantong University, Qidong Liver Cancer Institute, No.9, Seyuan Road, Chongchuan District, Nantong, Jiangsu, 226000, China
| | - Yun Niu
- Institute of Special Environmental Medicine, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Sitong Cao
- Institute of Special Environmental Medicine, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Chunsun Fan
- Qidong People's Hospital, Affiliated Qidong Hospital of Nantong University, Qidong Liver Cancer Institute, No.9, Seyuan Road, Chongchuan District, Nantong, Jiangsu, 226000, China
| | - Jian Fan
- Qidong People's Hospital, Affiliated Qidong Hospital of Nantong University, Qidong Liver Cancer Institute, No.9, Seyuan Road, Chongchuan District, Nantong, Jiangsu, 226000, China
| | - Li Zhu
- Institute of Special Environmental Medicine, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China.
| | - Xueting Wang
- Institute of Special Environmental Medicine, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China.
- Medical Research Center Affiliated Hospital 2 of Nantong University, Nantong, China.
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Syed F, Ballew O, Lee CC, Rana J, Krishnan P, Castela A, Weaver SA, Chalasani NS, Thomaidou SF, Demine S, Chang G, Coomans de Brachène A, Alvelos MI, Marselli L, Orr K, Felton JL, Liu J, Marchetti P, Zaldumbide A, Scheuner D, Eizirik DL, Evans-Molina C. Pharmacological inhibition of tyrosine protein-kinase 2 reduces islet inflammation and delays type 1 diabetes onset in mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.20.585925. [PMID: 38766166 PMCID: PMC11100605 DOI: 10.1101/2024.03.20.585925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Abstract
Tyrosine protein-kinase 2 (TYK2), a member of the Janus kinase family, mediates inflammatory signaling through multiple cytokines, including interferon-α (IFNα), interleukin (IL)-12, and IL-23. Missense mutations in TYK2 are associated with protection against type 1 diabetes (T1D), and inhibition of TYK2 shows promise in the management of other autoimmune conditions. Here, we evaluated the effects of specific TYK2 inhibitors (TYK2is) in pre-clinical models of T1D. First, human β cells, cadaveric donor islets, and iPSC-derived islets were treated in vitro with IFNα in combination with a small molecule TYK2i (BMS-986165 or a related molecule BMS-986202). TYK2 inhibition prevented IFNα-induced β cell HLA class I up-regulation, endoplasmic reticulum stress, and chemokine production. In co-culture studies, pre-treatment of β cells with a TYK2i prevented IFNα-induced activation of T cells targeting an epitope of insulin. In vivo administration of BMS-986202 in two mouse models of T1D (RIP-LCMV-GP mice and NOD mice) reduced systemic and tissue-localized inflammation, prevented β cell death, and delayed T1D onset. Transcriptional phenotyping of pancreatic islets, pancreatic lymph nodes (PLN), and spleen during early disease pathogenesis highlighted a role for TYK2 inhibition in modulating signaling pathways associated with inflammation, translational control, stress signaling, secretory function, immunity, and diabetes. Additionally, TYK2i treatment changed the composition of innate and adaptive immune cell populations in the blood and disease target tissues, resulting in an immune phenotype with a diminished capacity for β cell destruction. Overall, these findings indicate that TYK2i has beneficial effects in both the immune and endocrine compartments in models of T1D, thus supporting a path forward for testing TYK2 inhibitors in human T1D.
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Affiliation(s)
- Farooq Syed
- Indiana University School of Medicine, Indianapolis, Indiana, USA
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Pediatrics and the Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Olivia Ballew
- Indiana Biosciences Research Institute, Indianapolis, IN, USA
| | - Chih-Chun Lee
- Indiana University School of Medicine, Indianapolis, Indiana, USA
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Pediatrics and the Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Jyoti Rana
- Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Pediatrics and the Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Preethi Krishnan
- Indiana University School of Medicine, Indianapolis, Indiana, USA
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Angela Castela
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium
| | - Staci A. Weaver
- Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA
| | | | - Sofia F. Thomaidou
- Department of Cell and Chemical Biology, Leiden University Medical Center, The Netherlands
| | - Stephane Demine
- Indiana Biosciences Research Institute, Indianapolis, IN, USA
| | - Garrick Chang
- Department of Physics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, USA
| | | | - Maria Ines Alvelos
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium
| | - Lorella Marselli
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Kara Orr
- Indiana University School of Medicine, Indianapolis, Indiana, USA
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Pediatrics and the Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Jamie L. Felton
- Indiana University School of Medicine, Indianapolis, Indiana, USA
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Pediatrics and the Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Jing Liu
- Department of Physics and Astronomy, Purdue University, West Lafayette, IN, USA
| | - Piero Marchetti
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Arnaud Zaldumbide
- Department of Cell and Chemical Biology, Leiden University Medical Center, The Netherlands
| | | | - Decio L. Eizirik
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium
| | - Carmella Evans-Molina
- Indiana University School of Medicine, Indianapolis, Indiana, USA
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Pediatrics and the Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA
- Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA
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9
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Bruzzaniti S, Piemonte E, Lepore MT, Galgani M. Anti-viral innate immunity: Is it where type 1 diabetes really begins? Diabetes Metab Res Rev 2023:e3623. [PMID: 36764821 DOI: 10.1002/dmrr.3623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 01/17/2023] [Indexed: 02/12/2023]
Affiliation(s)
- Sara Bruzzaniti
- Institute Experimental Endocrinology and Oncology "G. Salvatore", National Research Council, Naples, Italy
| | - Erica Piemonte
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
| | - Maria Teresa Lepore
- Institute Experimental Endocrinology and Oncology "G. Salvatore", National Research Council, Naples, Italy
| | - Mario Galgani
- Institute Experimental Endocrinology and Oncology "G. Salvatore", National Research Council, Naples, Italy
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
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10
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Yang S, Zhao M, Jia S. Macrophage: Key player in the pathogenesis of autoimmune diseases. Front Immunol 2023; 14:1080310. [PMID: 36865559 PMCID: PMC9974150 DOI: 10.3389/fimmu.2023.1080310] [Citation(s) in RCA: 59] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 01/09/2023] [Indexed: 02/16/2023] Open
Abstract
The macrophage is an essential part of the innate immune system and also serves as the bridge between innate immunity and adaptive immune response. As the initiator and executor of the adaptive immune response, macrophage plays an important role in various physiological processes such as immune tolerance, fibrosis, inflammatory response, angiogenesis and phagocytosis of apoptotic cells. Consequently, macrophage dysfunction is a vital cause of the occurrence and development of autoimmune diseases. In this review, we mainly discuss the functions of macrophages in autoimmune diseases, especially in systemic lupus erythematosus (SLE), rheumatic arthritis (RA), systemic sclerosis (SSc) and type 1 diabetes (T1D), providing references for the treatment and prevention of autoimmune diseases.
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Affiliation(s)
- Shuang Yang
- Dapartment of Dermatology, Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ming Zhao
- Dapartment of Dermatology, Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.,Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China.,Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China
| | - Sujie Jia
- Department of Pharmacy, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
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11
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Piñeros AR, Kulkarni A, Gao H, Orr KS, Glenn L, Huang F, Liu Y, Gannon M, Syed F, Wu W, Anderson CM, Evans-Molina C, McDuffie M, Nadler JL, Morris MA, Mirmira RG, Tersey SA. Proinflammatory signaling in islet β cells propagates invasion of pathogenic immune cells in autoimmune diabetes. Cell Rep 2022; 39:111011. [PMID: 35767947 PMCID: PMC9297711 DOI: 10.1016/j.celrep.2022.111011] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Revised: 04/10/2022] [Accepted: 06/07/2022] [Indexed: 12/13/2022] Open
Abstract
Type 1 diabetes is a disorder of immune tolerance that leads to death of insulin-producing islet β cells. We hypothesize that inflammatory signaling within β cells promotes progression of autoimmunity within the islet microenvironment. To test this hypothesis, we deleted the proinflammatory gene encoding 12/15-lipoxygenase (Alox15) in β cells of non-obese diabetic mice at a pre-diabetic time point when islet inflammation is a feature. Deletion of Alox15 leads to preservation of β cell mass, reduces populations of infiltrating T cells, and protects against spontaneous autoimmune diabetes in both sexes. Mice lacking Alox15 in β cells exhibit an increase in a population of β cells expressing the gene encoding the protein programmed death ligand 1 (PD-L1), which engages receptors on immune cells to suppress autoimmunity. Delivery of a monoclonal antibody against PD-L1 recovers the diabetes phenotype in knockout animals. Our results support the contention that inflammatory signaling in β cells promotes autoimmunity during type 1 diabetes progression.
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Affiliation(s)
- Annie R Piñeros
- Department of Pediatrics and the Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Abhishek Kulkarni
- Department of Medicine and the Kovler Diabetes Center, The University of Chicago, Chicago, IL 60637, USA
| | - Hongyu Gao
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Kara S Orr
- Department of Pediatrics and the Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Lindsey Glenn
- Department of Medicine, Eastern Virginia Medical School, Norfolk, VA, USA
| | - Fei Huang
- Department of Medicine and the Kovler Diabetes Center, The University of Chicago, Chicago, IL 60637, USA
| | - Yunlong Liu
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Maureen Gannon
- Department of Medicine, Vanderbilt University and Department of Veterans Affairs, Tennessee Valley Authority, Nashville, TN, USA
| | - Farooq Syed
- Department of Pediatrics and the Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Wenting Wu
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Cara M Anderson
- Department of Medicine and the Kovler Diabetes Center, The University of Chicago, Chicago, IL 60637, USA
| | - Carmella Evans-Molina
- Department of Pediatrics and the Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA; Roudebush VA Medical Center, Indianapolis, IN, USA
| | - Marcia McDuffie
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, USA
| | - Jerry L Nadler
- Departments of Medicine and Pharmacology, New York Medical College, Valhalla, NY, USA
| | - Margaret A Morris
- Department of Medicine, Eastern Virginia Medical School, Norfolk, VA, USA
| | - Raghavendra G Mirmira
- Department of Medicine and the Kovler Diabetes Center, The University of Chicago, Chicago, IL 60637, USA.
| | - Sarah A Tersey
- Department of Medicine and the Kovler Diabetes Center, The University of Chicago, Chicago, IL 60637, USA.
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12
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Kulkarni A, Anderson CM, Mirmira RG, Tersey SA. Role of Polyamines and Hypusine in β Cells and Diabetes Pathogenesis. Metabolites 2022; 12:344. [PMID: 35448531 PMCID: PMC9028953 DOI: 10.3390/metabo12040344] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 04/04/2022] [Accepted: 04/06/2022] [Indexed: 02/04/2023] Open
Abstract
The polyamines-putrescine, spermidine, and spermine-are polycationic, low molecular weight amines with cellular functions primarily related to mRNA translation and cell proliferation. Polyamines partly exert their effects via the hypusine pathway, wherein the polyamine spermidine provides the aminobutyl moiety to allow posttranslational modification of the translation factor eIF5A with the rare amino acid hypusine (hydroxy putrescine lysine). The "hypusinated" eIF5A (eIF5Ahyp) is considered to be the active form of the translation factor necessary for the translation of mRNAs associated with stress and inflammation. Recently, it has been demonstrated that activity of the polyamines-hypusine circuit in insulin-producing islet β cells contributes to diabetes pathogenesis under conditions of inflammation. Elevated levels of polyamines are reported in both exocrine and endocrine cells of the pancreas, which may contribute to endoplasmic reticulum stress, oxidative stress, inflammatory response, and autophagy. In this review, we have summarized the existing research on polyamine-hypusine metabolism in the context of β-cell function and diabetes pathogenesis.
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Affiliation(s)
| | | | | | - Sarah A. Tersey
- Department of Medicine, The University of Chicago, Chicago, IL 60637, USA; (A.K.); (C.M.A.); (R.G.M.)
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13
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Rutsch N, Chamberlain CE, Dixon W, Spector L, Letourneau-Freiberg LR, Lwin WW, Philipson LH, Zarbock A, Saintus K, Wang J, German MS, Anderson MS, Lowell CA. Diabetes With Multiple Autoimmune and Inflammatory Conditions Linked to an Activating SKAP2 Mutation. Diabetes Care 2021; 44:1816-1825. [PMID: 34172489 PMCID: PMC8385470 DOI: 10.2337/dc20-2317] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 03/09/2021] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Multiple genome-wide association studies have identified a strong genetic linkage between the SKAP2 locus and type 1 diabetes (T1D), but how this leads to disease remains obscure. Here, we characterized the functional consequence of a novel SKAP2 coding mutation in a patient with T1D to gain further insight into how this impacts immune tolerance. RESEARCH DESIGN AND METHODS We identified a 24-year-old individual with T1D and other autoimmune and inflammatory conditions. The proband and first-degree relatives were recruited for whole-exome sequencing. Functional studies of the protein variant were performed using a cell line and primary myeloid immune cells collected from family members. RESULTS Sequencing identified a de novo SKAP2 variant (c.457G>A, p.Gly153Arg) in the proband. Assays using monocyte-derived macrophages from the individual revealed enhanced activity of integrin pathways and a migratory phenotype in the absence of chemokine stimulation, consistent with SKAP2 p.Gly153Arg being constitutively active. The p.Gly153Arg variant, located in the well-conserved lipid-binding loop, induced similar phenotypes when expressed in a human macrophage cell line. SKAP2 p.Gly153Arg is a gain-of-function, pathogenic mutation that disrupts myeloid immune cell function, likely resulting in a break in immune tolerance and T1D. CONCLUSIONS SKAP2 plays a key role in myeloid cell activation and migration. This particular mutation in a patient with T1D and multiple autoimmune conditions implicates a role for activating SKAP2 variants in autoimmune T1D.
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Affiliation(s)
- Niklas Rutsch
- Department of Laboratory Medicine, University of California, San Francisco, San Francisco, San Francisco, CA.,The Program in Immunology, University of California, San Francisco, San Francisco, San Francisco, CA.,Department of Anesthesiology, Intensive Care, and Pain Medicine, University Hospital Münster, University of Münster, Münster, Germany
| | - Chester E Chamberlain
- Diabetes Center, University of California, San Francisco, San Francisco, San Francisco, CA.,Department of Medicine, University of California, San Francisco, San Francisco, San Francisco, CA.,Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, San Francisco, CA
| | - Wesley Dixon
- Department of Laboratory Medicine, University of California, San Francisco, San Francisco, San Francisco, CA.,The Program in Immunology, University of California, San Francisco, San Francisco, San Francisco, CA
| | - Lauren Spector
- Department of Laboratory Medicine, University of California, San Francisco, San Francisco, San Francisco, CA.,The Program in Immunology, University of California, San Francisco, San Francisco, San Francisco, CA
| | - Lisa R Letourneau-Freiberg
- Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism and the Kovler Diabetes Center, The University of Chicago, Chicago, IL
| | - Wint W Lwin
- Diabetes Center, University of California, San Francisco, San Francisco, San Francisco, CA.,Department of Medicine, University of California, San Francisco, San Francisco, San Francisco, CA
| | - Louis H Philipson
- Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism and the Kovler Diabetes Center, The University of Chicago, Chicago, IL
| | - Alexander Zarbock
- Department of Anesthesiology, Intensive Care, and Pain Medicine, University Hospital Münster, University of Münster, Münster, Germany
| | - Karline Saintus
- Diabetes Center, University of California, San Francisco, San Francisco, San Francisco, CA.,Department of Medicine, University of California, San Francisco, San Francisco, San Francisco, CA.,Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, San Francisco, CA
| | - Juehu Wang
- Diabetes Center, University of California, San Francisco, San Francisco, San Francisco, CA.,Department of Medicine, University of California, San Francisco, San Francisco, San Francisco, CA.,Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, San Francisco, CA
| | - Michael S German
- Diabetes Center, University of California, San Francisco, San Francisco, San Francisco, CA .,Department of Medicine, University of California, San Francisco, San Francisco, San Francisco, CA.,Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, San Francisco, CA
| | - Mark S Anderson
- Diabetes Center, University of California, San Francisco, San Francisco, San Francisco, CA .,Department of Medicine, University of California, San Francisco, San Francisco, San Francisco, CA
| | - Clifford A Lowell
- Department of Laboratory Medicine, University of California, San Francisco, San Francisco, San Francisco, CA .,The Program in Immunology, University of California, San Francisco, San Francisco, San Francisco, CA
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14
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Kordyukova LV, Shanko AV. COVID-19: Myths and Reality. BIOCHEMISTRY. BIOKHIMIIA 2021; 86:800-817. [PMID: 34284707 PMCID: PMC8265000 DOI: 10.1134/s0006297921070026] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 04/28/2021] [Accepted: 04/28/2021] [Indexed: 02/06/2023]
Abstract
COVID-19, a new human respiratory disease that has killed nearly 3 million people in a year since the start of the pandemic, is a global public health challenge. Its infectious agent, SARS-CoV-2, differs from other coronaviruses in a number of structural features that make this virus more pathogenic and transmissible. In this review, we discuss some important characteristics of the main SARS-CoV-2 surface antigen, the spike (S) protein, such as (i) ability of the receptor-binding domain (RBD) to switch between the "standing-up" position (open pre-fusion conformation) for receptor binding and the "lying-down" position (closed pre-fusion conformation) for immune system evasion; (ii) advantage of a high binding affinity of the RBD open conformation to the human angiotensin-converting enzyme 2 (ACE2) receptor for efficient cell entry; and (iii) S protein preliminary activation by the intracellular furin-like proteases for facilitation of the virus spreading across different cell types. We describe interactions between the S protein and cellular receptors, co-receptors, and antagonists, as well as a hypothetical mechanism of the homotrimeric spike structure destabilization that triggers the fusion of the viral envelope with the cell membrane at physiological pH and mediates the viral nucleocapsid entry into the cytoplasm. The transition of the S protein pre-fusion conformation to the post-fusion one on the surface of virions after their treatment with some reagents, such as β-propiolactone, is essential, especially in relation to the vaccine production. We also compare the COVID-19 pathogenesis with that of severe outbreaks of "avian" influenza caused by the A/H5 and A/H7 highly pathogenic viruses and discuss the structural similarities between the SARS-CoV-2 S protein and hemagglutinins of those highly pathogenic strains. Finally, we touch on the prospective and currently used COVID-19 antiviral and anti-pathogenetic therapeutics, as well as recently approved conventional and innovative COVID-19 vaccines and their molecular and immunological features.
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Affiliation(s)
- Larisa V Kordyukova
- Belozersky Institute of Physicochemical Biology, Lomonosov Moscow State University, Moscow, 119991, Russia.
| | - Andrey V Shanko
- FORT LLC, R&D Department, Moscow, 119435, Russia
- Ivanovsky Institute of Virology, Gamaleya Federal Research Center for Epidemiology and Microbiology, Moscow, 123098, Russia
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15
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Henriques F, Bedard AH, Guilherme A, Kelly M, Chi J, Zhang P, Lifshitz LM, Bellvé K, Rowland LA, Yenilmez B, Kumar S, Wang Y, Luban J, Weinstein LS, Lin JD, Cohen P, Czech MP. Single-Cell RNA Profiling Reveals Adipocyte to Macrophage Signaling Sufficient to Enhance Thermogenesis. Cell Rep 2021; 32:107998. [PMID: 32755590 PMCID: PMC7433376 DOI: 10.1016/j.celrep.2020.107998] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 06/22/2020] [Accepted: 07/15/2020] [Indexed: 12/29/2022] Open
Abstract
Adipocytes deficient in fatty acid synthase (iAdFASNKO) emit signals that mimic cold exposure to enhance the appearance of thermogenic beige adipocytes in mouse inguinal white adipose tissues (iWATs). Both cold exposure and iAdFASNKO upregulate the sympathetic nerve fiber (SNF) modulator Neuregulin 4 (Nrg4), activate SNFs, and require adipocyte cyclic AMP/protein kinase A (cAMP/PKA) signaling for beige adipocyte appearance, as it is blocked by adipocyte Gsα deficiency. Surprisingly, however, in contrast to cold-exposed mice, neither iWAT denervation nor Nrg4 loss attenuated adipocyte browning in iAdFASNKO mice. Single-cell transcriptomic analysis of iWAT stromal cells revealed increased macrophages displaying gene expression signatures of the alternately activated type in iAdFASNKO mice, and their depletion abrogated iWAT beiging. Altogether, these findings reveal that divergent cellular pathways are sufficient to cause adipocyte browning. Importantly, adipocyte signaling to enhance alternatively activated macrophages in iAdFASNKO mice is associated with enhanced adipose thermogenesis independent of the sympathetic neuron involvement this process requires in the cold. Henriques et al. show an alternative pathway to enhance thermogenesis through an adipocyte cAMP/PKA axis in denervated iWAT. Signals emanating from this pathway generate M2-type macrophages associated with iWAT browning.
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Affiliation(s)
- Felipe Henriques
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA
| | - Alexander H Bedard
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA
| | - Adilson Guilherme
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA
| | - Mark Kelly
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA
| | - Jingyi Chi
- Laboratory of Molecular Metabolism, The Rockefeller University, New York, NY, USA
| | - Peng Zhang
- Life Sciences Institute, University of Michigan Medical Center, Ann Arbor, MI, USA; Department of Cell and Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI, USA
| | - Lawrence M Lifshitz
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA
| | - Karl Bellvé
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA
| | - Leslie A Rowland
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA
| | - Batuhan Yenilmez
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA
| | - Shreya Kumar
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA
| | - Yetao Wang
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA
| | - Jeremy Luban
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA
| | - Lee S Weinstein
- Metabolic Diseases Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Jiandie D Lin
- Life Sciences Institute, University of Michigan Medical Center, Ann Arbor, MI, USA; Department of Cell and Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI, USA
| | - Paul Cohen
- Laboratory of Molecular Metabolism, The Rockefeller University, New York, NY, USA
| | - Michael P Czech
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
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16
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Kim M, Huda MN, O'Connor A, Albright J, Durbin-Johnson B, Bennett BJ. Hepatic transcriptional profile reveals the role of diet and genetic backgrounds on metabolic traits in female progenitor strains of the Collaborative Cross. Physiol Genomics 2021; 53:173-192. [PMID: 33818129 PMCID: PMC8424536 DOI: 10.1152/physiolgenomics.00140.2020] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 03/23/2021] [Accepted: 03/26/2021] [Indexed: 12/28/2022] Open
Abstract
Mice have provided critical mechanistic understandings of clinical traits underlying metabolic syndrome (MetSyn) and susceptibility to MetSyn in mice is known to vary among inbred strains. We investigated the diet- and strain-dependent effects on metabolic traits in the eight Collaborative Cross (CC) founder strains (A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, NZO/HILtJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ). Liver transcriptomics analysis showed that both atherogenic diet and host genetics have profound effects on the liver transcriptome, which may be related to differences in metabolic traits observed between strains. We found strain differences in circulating trimethylamine N-oxide (TMAO) concentration and liver triglyceride content, both of which are traits associated with metabolic diseases. Using a network approach, we identified a module of transcripts associated with TMAO and liver triglyceride content, which was enriched in functional pathways. Interrogation of the module related to metabolic traits identified NADPH oxidase 4 (Nox4), a gene for a key enzyme in the production of reactive oxygen species, which showed a strong association with plasma TMAO and liver triglyceride. Interestingly, Nox4 was identified as the highest expressed in the C57BL/6J and NZO/HILtJ strains and the lowest expressed in the CAST/EiJ strain. Based on these results, we suggest that there may be genetic variation in the contribution of Nox4 to the regulation of plasma TMAO and liver triglyceride content. In summary, we show that liver transcriptomic analysis identified diet- or strain-specific pathways for metabolic traits in the Collaborative Cross (CC) founder strains.
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Affiliation(s)
- Myungsuk Kim
- Department of Nutrition, University of California, Davis, California
- USDA-ARS-Western Human Nutrition Research Center, Davis, California
| | - M Nazmul Huda
- Department of Nutrition, University of California, Davis, California
- USDA-ARS-Western Human Nutrition Research Center, Davis, California
| | - Annalouise O'Connor
- Nutrition Research Institute, University of North Carolina, Kannapolis, North Carolina
| | - Jody Albright
- Nutrition Research Institute, University of North Carolina, Kannapolis, North Carolina
| | | | - Brian J Bennett
- Department of Nutrition, University of California, Davis, California
- USDA-ARS-Western Human Nutrition Research Center, Davis, California
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17
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Parv K, Westerlund N, Merchant K, Komijani M, Lindsay RS, Christoffersson G. Phagocytosis and Efferocytosis by Resident Macrophages in the Mouse Pancreas. Front Endocrinol (Lausanne) 2021; 12:606175. [PMID: 34113315 PMCID: PMC8185276 DOI: 10.3389/fendo.2021.606175] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 04/28/2021] [Indexed: 12/31/2022] Open
Abstract
The tissue microenvironment in the mouse pancreas has been shown to promote very different polarizations of resident macrophages with islet-resident macrophages displaying an inflammatory "M1" profile and macrophages in the exocrine tissue mostly displaying an alternatively activated "M2" profile. The impact of this polarization on tissue homeostasis and diabetes development is unclear. In this study, the ability of pancreas-resident macrophages to phagocyte bacterial and endogenous debris was investigated. Mouse endocrine and exocrine tissues were separated, and tissue-resident macrophages were isolated by magnetic immunolabeling. Isolated macrophages were subjected to flow cytometry for polarization markers and qPCR for phagocytosis-related genes. Functional in vitro investigations included phagocytosis and efferocytosis assays using pH-sensitive fluorescent bacterial particles and dead fluorescent neutrophils, respectively. Intravital confocal imaging of in situ phagocytosis and efferocytosis in the pancreas was used to confirm findings in vivo. Gene expression analysis revealed no significant overall difference in expression of most phagocytosis-related genes in islet-resident vs. exocrine-resident macrophages included in the analysis. In this study, pancreas-resident macrophages were shown to differ in their ability to phagocyte bacterial and endogenous debris depending on their microenvironment. This difference in abilities may be one of the factors polarizing islet-resident macrophages to an inflammatory state since phagocytosis has been found to imprint macrophage heterogeneity. It remains unclear if this difference has any implications in the development of islet dysfunction or autoimmunity.
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Affiliation(s)
- Kristel Parv
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | | | - Kevin Merchant
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Milad Komijani
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Robin S. Lindsay
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Gustaf Christoffersson
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
- Science for Life Laboratory, Uppsala University, Uppsala, Sweden
- *Correspondence: Gustaf Christoffersson,
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18
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Hu W, Song X, Yu H, Sun J, Wang H, Zhao Y. Clinical Translational Potentials of Stem Cell-Derived Extracellular Vesicles in Type 1 Diabetes. Front Endocrinol (Lausanne) 2021; 12:682145. [PMID: 35095751 PMCID: PMC8789747 DOI: 10.3389/fendo.2021.682145] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 12/06/2021] [Indexed: 02/06/2023] Open
Abstract
Type 1 diabetes (T1D) is an organ-specific disease characterized by the deficiency of insulin caused by the autoimmune destruction of pancreatic islet β cells. Stem cell-based therapies play essential roles in immunomodulation and tissue regeneration, both of which hold great promise for treating many autoimmune dysfunctions. However, their clinical translational potential has been limited by ethical issues and cell transplant rejections. Exosomes are small extracellular vesicles (EVs) released by almost all types of cells, performing a variety of cell functions through the delivery of their molecular contents such as proteins, DNAs, and RNAs. Increasing evidence suggests that stem cell-derived EVs exhibit similar functions as their parent cells, which may represent novel therapeutic agents for the treatment of autoimmune diseases including T1D. In this review, we summarize the current research progresses of stem cell-derived EVs for the treatment of T1D.
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Affiliation(s)
- Wei Hu
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, United States
| | - Xiang Song
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, United States
| | - Haibo Yu
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, United States
| | - Jingyu Sun
- Department of Chemistry and Chemistry Biology, Stevens Institute of Technology, Hoboken, NJ, United States
| | - Hongjun Wang
- Department of Chemistry and Chemistry Biology, Stevens Institute of Technology, Hoboken, NJ, United States
| | - Yong Zhao
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, United States
- Throne Biotechnologies Inc., Paramus, NJ, United States
- *Correspondence: Yong Zhao,
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19
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Yi X, Cheng X. Understanding Competitive Endogenous RNA Network Mechanism in Type 1 Diabetes Mellitus Using Computational and Bioinformatics Approaches. Diabetes Metab Syndr Obes 2021; 14:3865-3945. [PMID: 34526791 PMCID: PMC8436179 DOI: 10.2147/dmso.s315488] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 07/24/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Type 1 diabetes mellitus (T1DM), an autoimmune disease with a genetic tendency, has an increasing prevalence. Long non-coding RNA (lncRNA) and circular RNA (circRNA) are receiving increasing attention in disease pathogenesis. However, their roles in T1DM are poorly understood. The present study aimed at identifying signature lncRNAs and circRNAs and investigating their roles in T1DM using the competing endogenous RNA (ceRNA) network analysis. METHODS The T1DM expression profile was downloaded from Gene Expression Omnibus (GEO) database to identify the differentially expressed circRNAs, lncRNAs, and mRNAs. The biological functions of these differentially expressed circRNAs, lncRNAs, and mRNAs were analyzed by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Targeting relationships of circRNA-miRNA, lncRNA-miRNA, and miRNA-mRNA were predicted, and the circRNA-lncRNA-miRNA-mRNA ceRNA regulatory network was established. Finally, qRT-PCR was applied to identify the effect of hsa_circ_0002202 inhibition on the IFN-I induced macrophage inflammation. RESULTS A total of 178 circRNAs, 404 lncRNAs, and 73 mRNAs were identified to be abnormally expressed in T1DM samples. Functional enrichment analysis results indicated that the differentially expressed genes were mainly enriched in extracellular matrix components and macrophage activation. CeRNA regulatory network showed that circRNAs and lncRNAs regulate mRNAs through integrate multiple miRNAs. In addition, in vitro experiments showed that hsa_circ_0002202 inhibition suppressed the type I interferon (IFN-I)-induced macrophage inflammation. CONCLUSION In the present study, the circRNA-lncRNA-miRNA-mRNA ceRNA regulatory network in T1DM was established for the first time. We also found that hsa_circ_0002202 inhibition suppressed the IFN-I-induced macrophage inflammation. Our study may lay a foundation for future studies on the ceRNA regulatory network in T1DM.
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Affiliation(s)
- Xuanzi Yi
- Department of Medicine II, Division of Endocrinology and Diabetology, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, 79106, Germany
- Correspondence: Xuanzi Yi Department of Medicine II, Division of Endocrinology and Diabetology, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, Freiburg, 79106, GermanyTel/Fax +49 761 270-73270 Email
| | - Xu Cheng
- Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China
- Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, 79106, Germany
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20
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Elhag DA, Kumar M, Al Khodor S. Exploring the Triple Interaction between the Host Genome, the Epigenome, and the Gut Microbiome in Type 1 Diabetes. Int J Mol Sci 2020; 22:ijms22010125. [PMID: 33374418 PMCID: PMC7795494 DOI: 10.3390/ijms22010125] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Revised: 12/13/2020] [Accepted: 12/15/2020] [Indexed: 12/11/2022] Open
Abstract
Type 1 diabetes (T1D) is an auto-immune disorder characterized by a complex interaction between the host immune system and various environmental factors in genetically susceptible individuals. Genome-wide association studies (GWAS) identified different T1D risk and protection alleles, however, little is known about the environmental factors that can be linked to these alleles. Recent evidence indicated that, among those environmental factors, dysbiosis (imbalance) in the gut microbiota may play a role in the pathogenesis of T1D, affecting the integrity of the gut and leading to systemic inflammation and auto-destruction of the pancreatic β cells. Several studies have identified changes in the gut microbiome composition in humans and animal models comparing T1D subjects with controls. Those changes were characterized by a higher abundance of Bacteroides and a lower abundance of the butyrate-producing bacteria such as Clostridium clusters IV and XIVa. The mechanisms by which the dysbiotic bacteria and/or their metabolites interact with the genome and/or the epigenome of the host leading to destructive autoimmunity is still not clear. As T1D is a multifactorial disease, understanding the interaction between different environmental factors such as the gut microbiome, the genetic and the epigenetic determinants that are linked with the early appearance of autoantibodies can expand our knowledge about the disease pathogenesis. This review aims to provide insights into the interaction between the gut microbiome, susceptibility genes, epigenetic factors, and the immune system in the pathogenesis of T1D.
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21
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Augsornworawat P, Millman JR. Single-cell RNA sequencing for engineering and studying human islets. CURRENT OPINION IN BIOMEDICAL ENGINEERING 2020; 16:27-33. [PMID: 33738370 PMCID: PMC7963276 DOI: 10.1016/j.cobme.2020.06.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The islets of Langerhans are complex tissues composed of several cell types that secrete hormones. Loss or dysfunction of the insulin-producing β cells leads to dysregulation of blood glucose levels, resulting in diabetes. A major goal in cellular engineering has been to generate β cells from stem cells for use in cell-based therapies. However, the presence of other cell types within these islets can mask important details about β cells when using population-level assays. Single-cell RNA sequencing have enabled transcriptional assessment of individual cells within mixed populations. These technologies allow for accurate assessment of specific cell types and subtypes of β cells. Studies investigating different stages of β cell maturity have led to several insights into understanding islet development and diabetes pathology. Here, we highlight the key findings from the use of single-cell RNA sequencing on stem cell-derived and primary human islet cells found in different maturation and diabetic states.
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Affiliation(s)
- Punn Augsornworawat
- Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, Campus Box 8127, 660 South Euclid Avenue, St. Louis, MO 63110, USA
- Department of Biomedical Engineering, Washington University in St. Louis, 1 Brookings Drive, St. Louis, MO 63130, USA
| | - Jeffrey R. Millman
- Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, Campus Box 8127, 660 South Euclid Avenue, St. Louis, MO 63110, USA
- Department of Biomedical Engineering, Washington University in St. Louis, 1 Brookings Drive, St. Louis, MO 63130, USA
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22
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Li Y, Kong W, Yang W, Patel RM, Casey EB, Okeyo-Owuor T, White JM, Porter SN, Morris SA, Magee JA. Single-Cell Analysis of Neonatal HSC Ontogeny Reveals Gradual and Uncoordinated Transcriptional Reprogramming that Begins before Birth. Cell Stem Cell 2020; 27:732-747.e7. [PMID: 32822583 PMCID: PMC7655695 DOI: 10.1016/j.stem.2020.08.001] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 06/21/2020] [Accepted: 07/31/2020] [Indexed: 12/14/2022]
Abstract
Fetal and adult hematopoietic stem cells (HSCs) have distinct proliferation rates, lineage biases, gene expression profiles, and gene dependencies. Although these differences are widely recognized, it is not clear how the transition from fetal to adult identity is coordinated. Here we show that murine HSCs and committed hematopoietic progenitor cells (HPCs) undergo a gradual, rather than precipitous, transition from fetal to adult transcriptional states. The transition begins prior to birth and is punctuated by a late prenatal spike in type I interferon signaling that promotes perinatal HPC expansion and sensitizes progenitors to the leukemogenic FLT3ITD mutation. Most other changes in gene expression and enhancer activation are imprecisely timed and poorly coordinated. Thus, heterochronic enhancer elements, and their associated transcripts, are activated independently of one another rather than as part of a robust network. This simplifies the regulatory programs that guide neonatal HSC/HPC ontogeny, but it creates heterogeneity within these populations.
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Affiliation(s)
- Yanan Li
- Department of Pediatrics, Division of Hematology and Oncology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA
| | - Wenjun Kong
- Department of Genetics, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA; Department of Developmental Biology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA; Center of Regenerative Medicine, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA
| | - Wei Yang
- Department of Genetics, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA
| | - Riddhi M Patel
- Department of Pediatrics, Division of Hematology and Oncology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA
| | - Emily B Casey
- Department of Pediatrics, Division of Hematology and Oncology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA
| | - Theresa Okeyo-Owuor
- Department of Pediatrics, Division of Hematology and Oncology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA
| | - J Michael White
- Department of Pathology and Immunobiology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA
| | - Shaina N Porter
- Department of Pediatrics, Division of Hematology and Oncology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA
| | - Samantha A Morris
- Department of Genetics, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA; Department of Developmental Biology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA; Center of Regenerative Medicine, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
| | - Jeffrey A Magee
- Department of Pediatrics, Division of Hematology and Oncology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA; Department of Genetics, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
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23
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Yang L, Han X, Zhang C, Sun C, Huang S, Xiao W, Gao Y, Liang Q, Luo F, Lu W, Fu J, Zhou Y. Hsa_circ_0060450 Negatively Regulates Type I Interferon-Induced Inflammation by Serving as miR-199a-5p Sponge in Type 1 Diabetes Mellitus. Front Immunol 2020; 11:576903. [PMID: 33133095 PMCID: PMC7550460 DOI: 10.3389/fimmu.2020.576903] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Accepted: 08/31/2020] [Indexed: 12/15/2022] Open
Abstract
Circular RNAs (circRNAs) constitute a class of covalently circular non-coding RNA molecules formed by 5′ and 3′ end back-splicing. The rapid development of bioinformatics and large-scale sequencing has led to the identification of functional circRNAs. Despite an overall upward trend, studies focusing on the roles of circRNAs in immune diseases remain relatively scarce. In the present study, we obtained a differential circRNA expression profile based on microarray analysis of peripheral blood mononuclear cells (PBMCs) in children with type 1 diabetes mellitus (T1DM). We characterized one differentially expressed circRNA back-spliced from the MYB Proto-Oncogene Like 2 (MYBL2) gene in patients with T1DM, termed as hsa_circ_0060450. Subsequent assays revealed that hsa_circ_0060450 can serve as the sponge of miR-199a-5p, release its target gene, Src homology 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2), encoded by the tyrosine-protein phosphatase non-receptor type 11 gene (PTPN11), and further suppress the JAK-STAT signaling pathway triggered by type I interferon (IFN-I) to inhibit macrophage-mediated inflammation, which indicates the important roles of circRNAs in T1DM and represents a promising therapeutic molecule in the treatment of T1DM.
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Affiliation(s)
- Lan Yang
- Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.,National Health Commission (NHC) Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China
| | - Xiao Han
- Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.,National Health Commission (NHC) Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China
| | - Caiyan Zhang
- Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.,National Health Commission (NHC) Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China
| | - Chengjun Sun
- Department of Pediatric Endocrinology and Inherited Metabolic Diseases, Children's Hospital of Fudan University, Shanghai, China
| | - Saihua Huang
- Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.,National Health Commission (NHC) Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China
| | - Wenfeng Xiao
- Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.,National Health Commission (NHC) Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China
| | - Yajing Gao
- Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.,National Health Commission (NHC) Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China
| | - Qiuyan Liang
- Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.,National Health Commission (NHC) Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China
| | - Feihong Luo
- Department of Pediatric Endocrinology and Inherited Metabolic Diseases, Children's Hospital of Fudan University, Shanghai, China
| | - Wei Lu
- Department of Pediatric Endocrinology and Inherited Metabolic Diseases, Children's Hospital of Fudan University, Shanghai, China
| | - Jinrong Fu
- Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Yufeng Zhou
- Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.,National Health Commission (NHC) Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China
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24
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Christoffersson G, Ratliff SS, von Herrath MG. Interference with pancreatic sympathetic signaling halts the onset of diabetes in mice. SCIENCE ADVANCES 2020; 6:6/35/eabb2878. [PMID: 33052874 PMCID: PMC7531904 DOI: 10.1126/sciadv.abb2878] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 07/13/2020] [Indexed: 05/04/2023]
Abstract
The notably lobular distribution of immune lesions in type 1 diabetes (T1D) has been hypothesized to be the result of innervation within the pancreas. To investigate whether neuroimmune interactions could explain this phenomenon, we explored the impact of sympathetic signaling in the RIP-LCMV-GP mouse model of autoimmune diabetes. In this model, the CD8+ T cell attack on β cells replicates a key pathogenic feature of human T1D. We found that inhibition of α1 adrenoceptors, ablation of sympathetic nerves, and surgical denervation all had a protective effect in this model, without affecting the systemic presence of β cell-reactive CD8+ T cells. In vivo multiphoton imaging revealed a local effect within pancreatic islets including limited infiltration of both macrophages and β cell-specific CD8+ T cells. Islet-resident macrophages expressed adrenoceptors and were responsive to catecholamines. Islet macrophages may therefore constitute a pivotal neuroimmune signaling relay and could be a target for future interventions in T1D.
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Affiliation(s)
- Gustaf Christoffersson
- La Jolla Institute for Immunology, La Jolla, CA 92037, USA.
- Department of Medical Cell Biology, Uppsala University, Uppsala 75237, Sweden
- Science for Life Laboratory, Uppsala University, Uppsala 75237, Sweden
| | | | - Matthias G von Herrath
- La Jolla Institute for Immunology, La Jolla, CA 92037, USA.
- Novo Nordisk Research Center, Seattle, WA 98109, USA
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25
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Blum SI, Tse HM. Innate Viral Sensor MDA5 and Coxsackievirus Interplay in Type 1 Diabetes Development. Microorganisms 2020; 8:microorganisms8070993. [PMID: 32635205 PMCID: PMC7409145 DOI: 10.3390/microorganisms8070993] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 07/01/2020] [Accepted: 07/01/2020] [Indexed: 12/12/2022] Open
Abstract
Type 1 diabetes (T1D) is a polygenic autoimmune disease characterized by immune-mediated destruction of insulin-producing β-cells. The concordance rate for T1D in monozygotic twins is ≈30-50%, indicating that environmental factors also play a role in T1D development. Previous studies have demonstrated that enterovirus infections such as coxsackievirus type B (CVB) are associated with triggering T1D. Prior to autoantibody development in T1D, viral RNA and antibodies against CVB can be detected within the blood, stool, and pancreata. An innate pathogen recognition receptor, melanoma differentiation-associated protein 5 (MDA5), which is encoded by the IFIH1 gene, has been associated with T1D onset. It is unclear how single nucleotide polymorphisms in IFIH1 alter the structure and function of MDA5 that may lead to exacerbated antiviral responses contributing to increased T1D-susceptibility. Binding of viral dsRNA via MDA5 induces synthesis of antiviral proteins such as interferon-alpha and -beta (IFN-α/β). Viral infection and subsequent IFN-α/β synthesis can lead to ER stress within insulin-producing β-cells causing neo-epitope generation, activation of β-cell-specific autoreactive T cells, and β-cell destruction. Therefore, an interplay between genetics, enteroviral infections, and antiviral responses may be critical for T1D development.
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26
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Role of type I interferons and innate immunity in systemic sclerosis: unbalanced activities on distinct cell types? Curr Opin Rheumatol 2020; 31:569-575. [PMID: 31436583 DOI: 10.1097/bor.0000000000000659] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
PURPOSE OF REVIEW The role of type I IFNs (IFN-I) in the promotion of autoimmunity has been well established. However, its role in the skin fibrosis of systemic sclerosis (SSc) is less clear. IFN-I can participate to tissue repair, and, here, we will consider the extent to which IFN-I's role in SSc skin fibrosis may reflect in part IFN-I functions during wound healing. RECENT FINDINGS Studies are beginning to delineate whether IFN-I has a protective or pathogenic role and how IFN-I affects tissue biology. Recent support for a pathogenic role came from a study depleting plasmacytoid dendritic cells during bleomycin-induced skin fibrosis. The depletion reduced the bleomycin-induced IFN-I-stimulated transcripts and both prevented and reversed fibrosis. Additionally, two recent articles, one identifying SSc endothelial cell injury markers and one showing repressed IFN signaling in SSc keratinocytes, suggest the possibility of unbalanced IFN-I activities on distinct cells types. SUMMARY Recent results support a pathogenic role for IFN-I in skin fibrosis, and recent studies along with others suggest a scenario whereby SSc skin damage results from too much IFN-I-activity driving vasculopathy in combination with too little IFN-I-mediated epidermal integrity and antifibrotic fibroblast phenotype.
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27
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Hong YQ, Wan B, Li XF. Macrophage regulation of graft- vs-host disease. World J Clin Cases 2020; 8:1793-1805. [PMID: 32518770 PMCID: PMC7262718 DOI: 10.12998/wjcc.v8.i10.1793] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Revised: 04/08/2020] [Accepted: 04/21/2020] [Indexed: 02/05/2023] Open
Abstract
Hematopoietic stem cell transplantation has become a curative choice of many hematopoietic malignancy, but graft-vs-host disease (GVHD) has limited the survival quality and overall survival of hematopoietic stem cell transplantation. Understanding of the immune cells’ reaction in pathophysiology of GVHD has improved, but a review on the role of macrophages in GVHD is still absent. Studies have observed that macrophage infiltration is associated with GVHD occurrence and development. In this review, we summarize and analyze the role of macrophages in GVHD based on pathophysiology of acute and chronic GVHD, focusing on the macrophage recruitment and infiltration, macrophage polarization, macrophage secretion, and especially interaction of macrophages with other immune cells. We could conclude that macrophage recruitment and infiltration contribute to both acute and chronic GVHD. Based on distinguishing pathology of acute and chronic GVHD, macrophages tend to show a higher M1/M2 ratio in acute GVHD and a lower M1/M2 ratio in chronic GVHD. However, the influence of dominant cytokines in GVHD is controversial and inconsistent with macrophage polarization. In addition, interaction of macrophages with alloreactive T cells plays an important role in acute GVHD. Meanwhile, the interaction among macrophages, B cells, fibroblasts, and CD4+ T cells participates in chronic GVHD development.
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Affiliation(s)
- Ya-Qun Hong
- Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Department of Hematology, Fujian Medical University Union Hospital, Fuzhou 350000, Fujian Province, China
| | - Bo Wan
- Faculty of Life Sciences and Medicine, King’s College London, London WC1N 3BG, United Kingdom
| | - Xiao-Fan Li
- Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Department of Hematology, Fujian Medical University Union Hospital, Fuzhou 350000, Fujian Province, China
- INSERM U1160, Hospital Saint Louis, Université Paris Diderot, Paris 94430, France
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28
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Infections as triggers of flares in systemic autoimmune diseases: novel innate immunity mechanisms. Curr Opin Rheumatol 2020; 31:525-531. [PMID: 31135383 DOI: 10.1097/bor.0000000000000630] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW The innate immune response (IIR) has to be immediate facing pathogens, and effective to induce a long-lasting adaptive immunity and immune memory. In genetically susceptible individuals, beyond a first defense, a chronically activated by infections IIR may represent a trigger for the onset or flares in systemic autoimmune diseases. This article reviews the recent scientific literature in this regard and highlights the key issues needing investigation. RECENT FINDINGS Thanks to its high specificity mediated by pattern recognition receptors, the IIR is not called unspecific anymore. The discovery of these increasingly accurate recognizing molecular mechanisms has also evidenced their involvement in breaking self-immune tolerance and to maintain chronic inflammation in autoimmune responses. Neutrophil extracellular traps (NETS) as the main source of antinuclear antibodies; the 'neutrophils-pDC activation loop' theory; and the Th1/Th2/Th17 misbalances induced by microbial products because of chronically activated innate immune cells, are some of the recent uncovered IIR origins involved in infectious-induced systemic autoimmune diseases. SUMMARY A deeper understanding of the genetic predisposition and the pathogen-derived factors responsible to exacerbate the IIR might potentially provide therapeutic targets to counteract flares in systemic autoimmune diseases. VIDEO ABSTRACT.
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29
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He W, Kapate N, Shields CW, Mitragotri S. Drug delivery to macrophages: A review of targeting drugs and drug carriers to macrophages for inflammatory diseases. Adv Drug Deliv Rev 2019; 165-166:15-40. [PMID: 31816357 DOI: 10.1016/j.addr.2019.12.001] [Citation(s) in RCA: 158] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2019] [Revised: 11/28/2019] [Accepted: 12/04/2019] [Indexed: 12/16/2022]
Abstract
Macrophages play a key role in defending against foreign pathogens, healing wounds, and regulating tissue homeostasis. Driving this versatility is their phenotypic plasticity, which enables macrophages to respond to subtle cues in tightly coordinated ways. However, when this coordination is disrupted, macrophages can aid the progression of numerous diseases, including cancer, cardiovascular disease, and autoimmune disease. The central link between these disorders is aberrant macrophage polarization, which misguides their functional programs, secretory products, and regulation of the surrounding tissue microenvironment. As a result of their important and deterministic roles in both health and disease, macrophages have gained considerable attention as targets for drug delivery. Here, we discuss the role of macrophages in the initiation and progression of various inflammatory diseases, summarize the leading drugs used to regulate macrophages, and review drug delivery systems designed to target macrophages. We emphasize strategies that are approved for clinical use or are poised for clinical investigation. Finally, we provide a prospectus of the future of macrophage-targeted drug delivery systems.
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Affiliation(s)
- Wei He
- John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA; Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Neha Kapate
- John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - C Wyatt Shields
- John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA
| | - Samir Mitragotri
- John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.
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30
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Baharlou H, Canete NP, Cunningham AL, Harman AN, Patrick E. Mass Cytometry Imaging for the Study of Human Diseases-Applications and Data Analysis Strategies. Front Immunol 2019; 10:2657. [PMID: 31798587 PMCID: PMC6868098 DOI: 10.3389/fimmu.2019.02657] [Citation(s) in RCA: 122] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 10/28/2019] [Indexed: 01/09/2023] Open
Abstract
High parameter imaging is an important tool in the life sciences for both discovery and healthcare applications. Imaging Mass Cytometry (IMC) and Multiplexed Ion Beam Imaging (MIBI) are two relatively recent technologies which enable clinical samples to be simultaneously analyzed for up to 40 parameters at subcellular resolution. Importantly, these "Mass Cytometry Imaging" (MCI) modalities are being rapidly adopted for studies of the immune system in both health and disease. In this review we discuss, first, the various applications of MCI to date. Second, due to the inherent challenge of analyzing high parameter spatial data, we discuss the various approaches that have been employed for the processing and analysis of data from MCI experiments.
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Affiliation(s)
- Heeva Baharlou
- The Westmead Institute for Medical Research, University of Sydney, Westmead, NSW, Australia
- Centre for Virus Research, The Westmead Institute for Medical Research, Westmead, NSW, Australia
| | - Nicolas P. Canete
- The Westmead Institute for Medical Research, University of Sydney, Westmead, NSW, Australia
- Centre for Virus Research, The Westmead Institute for Medical Research, Westmead, NSW, Australia
| | - Anthony L. Cunningham
- The Westmead Institute for Medical Research, University of Sydney, Westmead, NSW, Australia
- Centre for Virus Research, The Westmead Institute for Medical Research, Westmead, NSW, Australia
| | - Andrew N. Harman
- The Westmead Institute for Medical Research, University of Sydney, Westmead, NSW, Australia
- Centre for Virus Research, The Westmead Institute for Medical Research, Westmead, NSW, Australia
| | - Ellis Patrick
- The Westmead Institute for Medical Research, University of Sydney, Westmead, NSW, Australia
- School of Mathematics and Statistics, University of Sydney, Sydney, NSW, Australia
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Ma WT, Gao F, Gu K, Chen DK. The Role of Monocytes and Macrophages in Autoimmune Diseases: A Comprehensive Review. Front Immunol 2019; 10:1140. [PMID: 31178867 PMCID: PMC6543461 DOI: 10.3389/fimmu.2019.01140] [Citation(s) in RCA: 220] [Impact Index Per Article: 36.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 05/07/2019] [Indexed: 12/19/2022] Open
Abstract
Monocytes (Mo) and macrophages (Mϕ) are key components of the innate immune system and are involved in regulation of the initiation, development, and resolution of many inflammatory disorders. In addition, these cells also play important immunoregulatory and tissue-repairing roles to decrease immune reactions and promote tissue regeneration. Several lines of evidence have suggested a causal link between the presence or activation of these cells and the development of autoimmune diseases. In addition, Mo or Mϕ infiltration in diseased tissues is a hallmark of several autoimmune diseases. However, the detailed contributions of these cells, whether they actually initiate disease or perpetuate disease progression, and whether their phenotype and functional alteration are merely epiphenomena are still unclear in many autoimmune diseases. Additionally, little is known about their heterogeneous populations in different autoimmune diseases. Elucidating the relevance of Mo and Mϕ in autoimmune diseases and the associated mechanisms could lead to the identification of more effective therapeutic strategies in the future.
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Affiliation(s)
- Wen-Tao Ma
- Veterinary Immunology Laboratory, College of Veterinary Medicine, Northwest A&F University, Yangling, China.,School of Life Sciences, University of Science and Technology of China, Hefei, China
| | - Fei Gao
- Veterinary Immunology Laboratory, College of Veterinary Medicine, Northwest A&F University, Yangling, China
| | - Kui Gu
- Veterinary Immunology Laboratory, College of Veterinary Medicine, Northwest A&F University, Yangling, China
| | - De-Kun Chen
- Veterinary Immunology Laboratory, College of Veterinary Medicine, Northwest A&F University, Yangling, China
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