1
|
Givian A, Azizan A, Jamshidi A, Mahmoudi M, Farhadi E. Iron metabolism in rheumatic diseases. J Transl Autoimmun 2025; 10:100267. [PMID: 39867458 PMCID: PMC11763848 DOI: 10.1016/j.jtauto.2025.100267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Revised: 12/24/2024] [Accepted: 01/03/2025] [Indexed: 01/28/2025] Open
Abstract
Iron is a crucial element for living organism in terms of oxygen transport, hematopoiesis, enzymatic activity, mitochondrial respiratory chain function and also immune system function. The human being has evolved a mechanism to regulate body iron. In some rheumatic diseases such as rheumatoid arthritis (RA), systemic lupus erythematous (SLE), systemic sclerosis (SSc), ankylosing spondylitis (AS), and gout, this balanced iron regulation is impaired. Altered iron homeostasis can contribute to disease progression through ROS production, fibrosis, inflammation, abnormal bone homeostasis, NETosis and cell senescence. In this review, we have focused on the iron metabolism in rheumatic disease and its role in disease progression.
Collapse
Affiliation(s)
- Aliakbar Givian
- Rheumatology Research Center, Tehran University of Medical Science, Tehran, Iran
- Department of Immunology, School of Medicine, Semnan University of Medical Science, Semnan, Iran
| | - Amin Azizan
- Rheumatology Research Center, Tehran University of Medical Science, Tehran, Iran
- Research Center for Chronic Inflammatory Diseases, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahmadreza Jamshidi
- Rheumatology Research Center, Tehran University of Medical Science, Tehran, Iran
| | - Mahdi Mahmoudi
- Rheumatology Research Center, Tehran University of Medical Science, Tehran, Iran
- Research Center for Chronic Inflammatory Diseases, Tehran University of Medical Sciences, Tehran, Iran
| | - Elham Farhadi
- Rheumatology Research Center, Tehran University of Medical Science, Tehran, Iran
- Research Center for Chronic Inflammatory Diseases, Tehran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
2
|
Liu Y, Li D, Zhang T, Wang K, Liang X, Zong X, Yang H, Li Z. Effect of imatinib on lipopolysaccharide‑induced acute lung injury and endothelial dysfunction through the P38 MAPK and NF-κB signaling pathways in vivo and in vitro. Respir Physiol Neurobiol 2025; 333:104388. [PMID: 39725368 DOI: 10.1016/j.resp.2024.104388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 12/16/2024] [Accepted: 12/24/2024] [Indexed: 12/28/2024]
Abstract
BACKGROUND The primary purpose of this study was to demonstrate the preventive effects of imatinib (IMA) on lipopolysaccharide (LPS)-induced inflammation in a mouse model of acute lung injury (ALI) and human umbilical vascular endothelial cells. METHODS LPS stimulation for 24 h induced ALI and cell inflammation. The pathological results of the lungs were evaluated using the wet/dry weight ratio, pulmonary vascular permeability measurements, and myeloperoxidase immunohistochemistry. The expression of pro-inflammatory mediators was analyzed using RT-PCR and enzyme-linked immunosorbent assay. Protein levels were analyzed using western blotting. The structure of cell junctions was detected using immunofluorescence. RESULTS IMA improved LPS-induced pulmonary pathological damage and reduced the lung wet/dry weight ratio and myeloperoxidase expression in the lung tissue. IMA decreased bronchoalveolar lavage fluid inflammatory cell count and the release of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and monocyte chemotactic protein 1 (MCP-1) in the blood. Pretreatment of human umbilical vascular endothelial cells with IMA significantly attenuated LPS-induced actin stress fiber formation and vascular endothelial-cadherin disruption. In addition, IMA downregulated the mRNA abundances of vascular cell adhesion molecule 1, intercellular adhesion molecule 1, IL-1β, IL-6, and tumor necrosis factor-α(TNF-α) expression. The phosphorylation of p65, nuclear factor-kappa B inhibitor alpha (IκBα), p38, extracellular signal-regulated kinase, and Jun N-terminal kinase induced by LPS were attenuated after IMA treatment in vivo and in vitro. CONCLUSIONS IMA modulates the nuclear factor-kappa B and mitogen-activated protein kinase signaling pathways and the production of pro-inflammatory cytokines to prevent cellular damage due to LPS infection. These results indicate that IMA may be a potential modulator of LPS-induced ALI.
Collapse
Affiliation(s)
- Yaru Liu
- Department of Emergency Medicine,The Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Duanyang Li
- Department of Emergency Medicine,The Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Tianyi Zhang
- Department of Emergency Medicine,The Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Keruo Wang
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin 300211 China
| | - Xue Liang
- Tianjin Institute of Cardiology, Tianjin 300211,China
| | - Xiaolong Zong
- Department of Clinical Laboratory, The Second Hospital of Tianjin Medical University, Tianjin 300211,China
| | - Hong Yang
- School of Biomedical Engineering and The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China.
| | - Zhenyu Li
- Department of Emergency Medicine,The Second Hospital of Tianjin Medical University, Tianjin 300211, China.
| |
Collapse
|
3
|
Retter A, Singer M, Annane D. "The NET effect": Neutrophil extracellular traps-a potential key component of the dysregulated host immune response in sepsis. Crit Care 2025; 29:59. [PMID: 39905519 DOI: 10.1186/s13054-025-05283-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 01/16/2025] [Indexed: 02/06/2025] Open
Abstract
Neutrophils release neutrophil extracellular traps (NETs) as part of a healthy host immune response. NETs physically trap and kill pathogens as well as activating and facilitating crosstalk between immune cells and complement. Excessive or inadequately resolved NETs are implicated in the underlying pathophysiology of sepsis and other inflammatory diseases, including amplification of the inflammatory response and inducing thrombotic complications. Here, we review the growing evidence implicating neutrophils and NETs as central players in the dysregulated host immune response. We discuss potential strategies for modifying NETs to improve patient outcomes and the need for careful patient selection.
Collapse
Affiliation(s)
- Andrew Retter
- Critical Care, Guy's and St Thomas' NHS Foundation Trust, London, UK.
- School of Immunology and Microbial Sciences, King's College, London, UK.
- Volition, London, UK.
| | - Mervyn Singer
- Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, UK
| | - Djillali Annane
- Department of Intensive Care, Raymond Poincaré Hospital, APHP University Versailles Saint Quentin-University Paris Saclay, INSERM, Garches, France
- IHU PROMETHEUS, Comprehensive Sepsis Center, Garches, France
- University Versailles Saint Quentin-University Paris Saclay, INSERM, Garches, France
- FHU SEPSIS (Saclay and Paris Seine Nord Endeavour to PerSonalize Interventions for Sepsis), Garches, France
| |
Collapse
|
4
|
Rodrigues KB, Weng Z, Graham ZA, Lavin K, McAdam J, Tuggle SC, Peoples B, Seay R, Yang S, Bamman MM, Broderick TJ, Montgomery SB. Exercise intensity and training alter the innate immune cell type and chromosomal origins of circulating cell-free DNA in humans. Proc Natl Acad Sci U S A 2025; 122:e2406954122. [PMID: 39805013 PMCID: PMC11761974 DOI: 10.1073/pnas.2406954122] [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: 05/05/2024] [Accepted: 11/06/2024] [Indexed: 01/16/2025] Open
Abstract
Exercising regularly promotes health, but these benefits are complicated by acute inflammation induced by exercise. A potential source of inflammation is cell-free DNA (cfDNA), yet the cellular origins, molecular causes, and immune system interactions of exercise-induced cfDNA are unclear. To study these, 10 healthy individuals were randomized to a 12-wk exercise program of either high-intensity tactical training (HITT) or traditional moderate-intensity training (TRAD). Blood plasma was collected pre- and postexercise at weeks 0 and 12 and after 4 wk of detraining upon program completion. Whole-genome enzymatic methylation sequencing (EM-seq) with cell-type proportion deconvolution was applied to cfDNA obtained from the 50 plasma samples and paired to concentration measurements for 90 circulating cytokines. Acute exercise increased the release of cfDNA from neutrophils, dendritic cells (DCs), and macrophages proportional to exercise intensity. Exercise training reduced cfDNA released in HITT participants but not TRAD and from DCs and macrophages but not neutrophils. For most participants, training lowered mitochondrial cfDNA at rest, even after detraining. Using a sequencing analysis approach we developed, we concluded that rapid ETosis, a process of cell death where cells release DNA extracellular traps, was the likely source of cfDNA, demonstrated by enrichment of nuclear DNA. Further, several cytokines were induced by acute exercise, such as IL-6, IL-10, and IL-16, and training attenuated the induction of only IL-6 and IL-17F. Cytokine levels were not associated with cfDNA induction, suggesting that these cytokines are not the main cause of exercise-induced cfDNA. Overall, exercise intensity and training modulated cfDNA release and cytokine responses, contributing to the anti-inflammatory effects of regular exercise.
Collapse
Affiliation(s)
- Kameron B. Rodrigues
- Department of Pathology, Stanford University School of Medicine, Stanford, CA94305
| | - Ziming Weng
- Department of Pathology, Stanford University School of Medicine, Stanford, CA94305
| | - Zachary A. Graham
- Healthspan, Resilience and Performance Research, Florida Institute for Human and Machine Cognition, Pensacola, FL32502
| | - Kaleen Lavin
- Healthspan, Resilience and Performance Research, Florida Institute for Human and Machine Cognition, Pensacola, FL32502
| | - Jeremy McAdam
- Healthspan, Resilience and Performance Research, Florida Institute for Human and Machine Cognition, Pensacola, FL32502
| | - S. Craig Tuggle
- Healthspan, Resilience and Performance Research, Florida Institute for Human and Machine Cognition, Pensacola, FL32502
| | - Brandon Peoples
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL35294
| | - Regina Seay
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL35294
| | - Sufen Yang
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL35294
| | - Marcas M. Bamman
- Healthspan, Resilience and Performance Research, Florida Institute for Human and Machine Cognition, Pensacola, FL32502
| | - Timothy J. Broderick
- Healthspan, Resilience and Performance Research, Florida Institute for Human and Machine Cognition, Pensacola, FL32502
| | | |
Collapse
|
5
|
Mercado-Evans V, Branthoover H, Chew C, Serchejian C, Saltzman AB, Mejia ME, Zulk JJ, Cornax I, Nizet V, Patras KA. Tamm-Horsfall protein augments neutrophil NETosis during urinary tract infection. JCI Insight 2025; 10:e180024. [PMID: 39589812 PMCID: PMC11721310 DOI: 10.1172/jci.insight.180024] [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: 02/05/2024] [Accepted: 11/19/2024] [Indexed: 11/28/2024] Open
Abstract
Urinary neutrophils are a hallmark of urinary tract infection (UTI), yet the mechanisms governing their activation, function, and efficacy in controlling infection remain incompletely understood. Tamm-Horsfall glycoprotein (THP), the most abundant protein in urine, uses terminal sialic acids to bind an inhibitory receptor and dampen neutrophil inflammatory responses. We hypothesized that neutrophil modulation is an integral part of THP-mediated host protection. In a UTI model, THP-deficient mice showed elevated urinary tract bacterial burdens, increased neutrophil recruitment, and more severe tissue histopathological changes compared with WT mice. Furthermore, THP-deficient mice displayed impaired urinary NETosis during UTI. To investigate the effect of THP on NETosis, we coupled in vitro fluorescence-based NET assays, proteomic analyses, and standard and imaging flow cytometry with peripheral human neutrophils. We found that THP increases proteins involved in respiratory chain, neutrophil granules, and chromatin remodeling pathways; enhances NETosis in an ROS-dependent manner; and drives NET-associated morphologic features including nuclear decondensation. These effects were observed only in the presence of a NETosis stimulus and could not be solely replicated with equivalent levels of sialic acid alone. We conclude that THP is a critical regulator of NETosis in the urinary tract, playing a key role in host defense against UTI.
Collapse
Affiliation(s)
- Vicki Mercado-Evans
- Department of Molecular Virology and Microbiology
- Medical Scientist Training Program
| | | | | | | | - Alexander B. Saltzman
- Mass Spectrometry Proteomics Core, Baylor College of Medicine (BCM), Houston, Texas, USA
| | | | | | | | - Victor Nizet
- Department of Pediatrics and
- Skaggs School of Pharmacy and Pharmaceutical Sciences, UCSD, La Jolla, California, USA
| | - Kathryn A. Patras
- Department of Molecular Virology and Microbiology
- Department of Pediatrics and
- Alkek Center for Metagenomics and Microbiome Research, BCM, Houston, Texas, USA
| |
Collapse
|
6
|
Zhang S, Wang Z, Zhang Y, Dong X, Zhu Q, Yuan C, Lu G, Gong W, Bi Y, Wang Y. LASP1 inhibits the formation of NETs and alleviates acute pancreatitis by stabilizing F-actin polymerization in neutrophils. Biochem Biophys Res Commun 2025; 744:151134. [PMID: 39708397 DOI: 10.1016/j.bbrc.2024.151134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 11/29/2024] [Accepted: 12/03/2024] [Indexed: 12/23/2024]
Abstract
BACKGROUND Neutrophil extracellular traps (NETs) play a significant role in the development of acute pancreatitis (AP). The actin-binding protein LASP1 regulates proteins associated with the cytoskeleton, yet its precise involvement in NETs and AP remains to be elucidated. METHODS To investigate the role of LASP1 in NETs and AP, several bioinformatics methods, such as weighted gene co-expression network analysis (WGCNA), differential analysis, and least absolute shrinkage and selection operator (LASSO) regression, were utilized to screen for feature genes based on the Gene Expression Omnibus (GEO) dataset. To further assess the impact of LASP1, both an in vitro model of 12-myristic-13-acetate phobolol (PMA)-induced NETs and a caerulein-induced AP model were employed. RESULTS Through WGCNA, AP-related module genes were screened, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses were conducted to identify enriched pathways and functions. Six characteristic genes were identified through LASSO regression screening, with LASP1 being the most distinct. LASP1 reduces the generation of NETs induced by PMA in vitro. Mechanistically, LASP1 may increase F-actin protein levels by inhibiting the depolymerization of F-actin. Furthermore, our study utilizing a mouse AP model demonstrated that the LSAP1 recombinant protein effectively alleviated pancreatic necrosis in mice afflicted with AP. CONCLUSION LASP1 inhibits the formation of NETs and may alleviate AP by increasing the level of F-actin protein.
Collapse
Affiliation(s)
- Siqin Zhang
- Department of Gastroenterology, Kunshan Hospital of Traditional Chinese Medicine, Yangzhou University, Kunshan, Suzhou, Jiangsu, China; Department of Gastroenterology, Pancreatic Center, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu, China
| | - Zhihao Wang
- Department of Gastroenterology, Pancreatic Center, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu, China
| | - Yuyan Zhang
- Department of Gastroenterology, Pancreatic Center, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu, China
| | - Xiaowu Dong
- Department of Gastroenterology, Pancreatic Center, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu, China
| | - Qingtian Zhu
- Department of Gastroenterology, Pancreatic Center, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu, China
| | - Chenchen Yuan
- Department of Gastroenterology, Pancreatic Center, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu, China
| | - Guotao Lu
- Department of Gastroenterology, Pancreatic Center, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu, China
| | - Weijuan Gong
- Department of Basic Medicine, School of Medicine, Yangzhou University, Yangzhou, Jiangsu, China
| | - Yawei Bi
- Department of Gastroenterology, Chinese PLA General Hospital First Medical Center, Beijing, China
| | - Yaodong Wang
- Department of Gastroenterology, Kunshan Hospital of Traditional Chinese Medicine, Yangzhou University, Kunshan, Suzhou, Jiangsu, China.
| |
Collapse
|
7
|
Gómez-Gaviria M, Baruch-Martínez DA, Mora-Montes HM. Exploring the Biology, Virulence, and General Aspects of Candida dubliniensis. Infect Drug Resist 2024; 17:5755-5773. [PMID: 39722735 PMCID: PMC11669290 DOI: 10.2147/idr.s497862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 12/09/2024] [Indexed: 12/28/2024] Open
Abstract
Fungal infections have become a growing public health concern, aggravated by the emergence of new pathogenic species and increasing resistance to antifungal drugs. The most common candidiasis is caused by Candida albicans; however, Candida dubliniensis has become an emerging opportunistic pathogen, and although less prevalent, it can cause superficial and systemic infections, especially in immunocompromised individuals. This yeast can colonize the oral cavity, skin, and other tissues, and has been associated with oral infections in patients with human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS), making it difficult to treat. The special interest in the study of this species lies in its ability to evade commonly used antifungal drugs, such as fluconazole, under different concentrations. In addition, it is difficult to identify because it can be confused with the species C. albicans, which could interfere with adequate treatment. Although the study of virulence factors in C. dubliniensis is limited, proteomic comparisons with C. albicans indicate that these virulence factors could be similar between the two species. However, differences could exist considering the evolutionary processes and lifestyle of each species. In this study, a detailed review of the current literature on C. dubliniensis was conducted, considering aspects such as biology, possible virulence factors, immune response, pathogen-host interaction, diagnosis, and treatment.
Collapse
Affiliation(s)
- Manuela Gómez-Gaviria
- Departamento de Biología, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Guanajuato, Gto, Mexico
| | - Dario A Baruch-Martínez
- Departamento de Biología, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Guanajuato, Gto, Mexico
| | - Héctor M Mora-Montes
- Departamento de Biología, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Guanajuato, Gto, Mexico
| |
Collapse
|
8
|
Prendecki M, Gurung A, Pisacano N, Pusey CD. The role of neutrophils in ANCA-associated vasculitis. Immunol Lett 2024; 270:106933. [PMID: 39362307 DOI: 10.1016/j.imlet.2024.106933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 09/23/2024] [Accepted: 09/30/2024] [Indexed: 10/05/2024]
Abstract
Anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) is a group of rare systemic autoimmune diseases characterised by necrotising inflammation of small blood vessels and usually associated with circulating ANCA. The pathophysiology of AAV is complex, involving many aspects of the innate and adaptive immune system. Neutrophils are central to the pathogenesis of AAV as they are both the target of the autoantibody and effector cells mediating vascular injury. We describe mechanisms for ANCA induced activation of neutrophils, the pathogenic mechanisms by which this leads to endothelial cell injury, and how neutrophil crosstalk modulates other aspects of the immune system in AAV.
Collapse
Affiliation(s)
- Maria Prendecki
- Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, United Kingdom.
| | - Angila Gurung
- Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, United Kingdom
| | - Noelle Pisacano
- Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, United Kingdom
| | - Charles D Pusey
- Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, United Kingdom
| |
Collapse
|
9
|
da Silva Pinto L, Junior RSA, Lopes BRP, da Silva GS, de Lima Menezes G, Moreira P, de Oliveira J, da Silva RA, Lousa D, Toledo KA. MPO interacts with hRSV particles, contributing to the virucidal effects of NETs against clinical and laboratory hRSV isolates. Int J Biol Macromol 2024; 283:137423. [PMID: 39537074 DOI: 10.1016/j.ijbiomac.2024.137423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 10/20/2024] [Accepted: 11/06/2024] [Indexed: 11/16/2024]
Abstract
Human Respiratory syncytial virus (hRSV) mainly affects immunosuppressed patients requiring hospitalization. No specific treatment is financially accessible, and available vaccines do not cover all risk groups. During hRSV infection, there is a robust neutrophilic influx into the airways. hRSV-activated neutrophils release substantial neutrophil extracellular traps (NETs) in lung tissue, comprising DNA, histones, cytosolic, and granular proteins. NETs form mucus buildup in the lungs, compromising respiratory capacity and neutralizing viral particles. Understanding responsible NETs molecules requires improvement. We evaluated NETs interacting with hRSV particles and their contribution to anti-hRSV NET effects. Immunoblotting, immunoprecipitation, and peptide sequencing assays confirmed hRSV binding to a 50-75 kDa NET protein, Myeloperoxidase (MPO). MPO, a microbicide enzyme in NETs, interacts with hRSV, likely at F0 protein (site IV) on the viral surface. Additionally, MPO (32 μM) and NETs (0.4 μg/mL) reduced in vitro replication of clinical (hRSV A and B) and laboratory (Long) hRSV isolates by approximately 30 %, reversible by selective MPO inhibitor (PF-06281355; 48 μM). Thus, MPO contributes to virucidal NET effects on diverse hRSV strains, enhancing comprehension of NETs' role in infection and aiding treatment strategies for respiratory diseases.
Collapse
Affiliation(s)
- Leonardo da Silva Pinto
- São Paulo State University (UNESP), School of Sciences, Humanities and Languages, Assis, Brazil
| | - Ronaldo Silva Alves Junior
- São Paulo State University (UNESP), School of Sciences, Humanities and Languages, Assis, Brazil; São Paulo State University (UNESP), Institute of Biosciences, Humanities and Exact Sciences, São José do Rio Preto, SP, Brazil
| | - Bruno Rafael Pereira Lopes
- São Paulo State University (UNESP), School of Sciences, Humanities and Languages, Assis, Brazil; São Paulo State University (UNESP), Institute of Biosciences, Humanities and Exact Sciences, São José do Rio Preto, SP, Brazil
| | - Gabriel Soares da Silva
- São Paulo State University (UNESP), School of Sciences, Humanities and Languages, Assis, Brazil
| | - Gabriela de Lima Menezes
- Biosystems Collaborative Nucleus, Institute of Exact Sciences, Federal University of Jatai, Jatai-GO, Brazil
| | - Pedro Moreira
- Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal; Centro de Engenharia Biológica, Escola de Engenharia da Universidade do Minho, Braga, Portugal
| | - Juliana de Oliveira
- São Paulo State University (UNESP), School of Sciences, Humanities and Languages, Assis, Brazil; Graduate Program in Applied and Computational Mathematics - PGMAC - State University of Londrina, Londrina, PR, Brazil
| | - Roosevelt Alves da Silva
- Biosystems Collaborative Nucleus, Institute of Exact Sciences, Federal University of Jatai, Jatai-GO, Brazil
| | - Diana Lousa
- Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal
| | - Karina Alves Toledo
- São Paulo State University (UNESP), School of Sciences, Humanities and Languages, Assis, Brazil; São Paulo State University (UNESP), Institute of Biosciences, Humanities and Exact Sciences, São José do Rio Preto, SP, Brazil.
| |
Collapse
|
10
|
Ramos Cáceres E, Kemperman L, Bonger KM. Environment-sensitive turn-on fluorescent probe enables live cell imaging of myeloperoxidase activity during NETosis. Commun Chem 2024; 7:262. [PMID: 39533026 PMCID: PMC11557929 DOI: 10.1038/s42004-024-01338-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Accepted: 10/24/2024] [Indexed: 11/16/2024] Open
Abstract
Myeloperoxidase (MPO) plays an important role in the immune response of human neutrophils and has been implicated in autoimmune conditions, cardiovascular disorders, and neurodegeneration. Current methods to detect MPO activity rely on the detection of HOCl using activatable probes or require challenging experimental procedures. Therefore, these tools provide limited information about the dynamics and localization of MPO in complex molecular processes such as NETosis in real time. In this study, we report a ''turn-on" activity-based probe that fluoresces exclusively upon binding to MPO, exhibits minimal background fluorescence in buffered aqueous media, and is blocked by MPO inhibitors. Our probe facilitates real-time imaging of direct MPO activity in human neutrophils and HL-60-derived granulocytes during NETosis under wash-free conditions. Furthermore, it allows for the discrimination between different triggers of NETosis in human neutrophils. These findings hold promise for advancing our understanding of the role of MPO in immune responses and inflammatory conditions.
Collapse
Affiliation(s)
- Enebie Ramos Cáceres
- Department of Synthetic Organic Chemistry, Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525AJ, Nijmegen, The Netherlands
| | - Lotte Kemperman
- Department of Synthetic Organic Chemistry, Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525AJ, Nijmegen, The Netherlands
| | - Kimberly M Bonger
- Department of Synthetic Organic Chemistry, Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525AJ, Nijmegen, The Netherlands.
| |
Collapse
|
11
|
Enochs C, Colpo GD, Couture L, Baskin L, Cahuiche AE, Lee EA, Nimjee S, McCullough LD. The Contribution of Neutrophil Extracellular Traps to Coagulopathy in Patients with COVID-19-Related Thrombosis. Viruses 2024; 16:1677. [PMID: 39599792 PMCID: PMC11598969 DOI: 10.3390/v16111677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 10/21/2024] [Accepted: 10/25/2024] [Indexed: 11/29/2024] Open
Abstract
COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is associated with hypercoagulability and increased incidence of thrombotic events. In this study, we investigated the levels of neutrophil extracellular trap biomarkers and von Willebrand factor to assess if these could predict the occurrence of a thrombotic event in COVID-19 patients. We enrolled 202 patients hospitalized with symptomatic COVID-19 infection. Of those, 104 patients did not experience any type of thrombotic events before or during their hospitalization. These patients were compared to the other cohort of 98, who experienced thrombotic events before or during their hospitalization. In total, 61 patients who experienced thrombotic events had the event after initial blood collection, so the predictive capacity of biomarkers in these patients was evaluated. Citrullinated histone H3 was the best predictive biomarker for thrombotic events in COVID-19 regardless of age, sex, and race; disease severity was also a significant predictor in most thrombotic event groups. These results may better inform treatment and prophylaxis of thrombotic events in COVID-19 and similar viral illnesses in the future to improve outcomes and reduce mortality.
Collapse
Affiliation(s)
- Carolyn Enochs
- Department of Neurology, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX 77030, USA; (C.E.); (G.D.C.); (L.B.); (A.E.C.); (E.A.L.); (L.D.M.)
| | - Gabriela Delevati Colpo
- Department of Neurology, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX 77030, USA; (C.E.); (G.D.C.); (L.B.); (A.E.C.); (E.A.L.); (L.D.M.)
| | - Lucy Couture
- Department of Neurology, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX 77030, USA; (C.E.); (G.D.C.); (L.B.); (A.E.C.); (E.A.L.); (L.D.M.)
| | - Lynae Baskin
- Department of Neurology, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX 77030, USA; (C.E.); (G.D.C.); (L.B.); (A.E.C.); (E.A.L.); (L.D.M.)
| | - Ana E. Cahuiche
- Department of Neurology, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX 77030, USA; (C.E.); (G.D.C.); (L.B.); (A.E.C.); (E.A.L.); (L.D.M.)
| | - Eunyoung Angela Lee
- Department of Neurology, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX 77030, USA; (C.E.); (G.D.C.); (L.B.); (A.E.C.); (E.A.L.); (L.D.M.)
| | - Shahid Nimjee
- Neurosurgery, The Ohio State University Medical Center, Columbus, OH 43210, USA;
| | - Louise D. McCullough
- Department of Neurology, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX 77030, USA; (C.E.); (G.D.C.); (L.B.); (A.E.C.); (E.A.L.); (L.D.M.)
| |
Collapse
|
12
|
Areny-Balagueró A, Camprubí-Rimblas M, Campaña-Duel E, Solé-Porta A, Ceccato A, Roig A, Laffey JG, Closa D, Artigas A. Priming Mesenchymal Stem Cells with Lipopolysaccharide Boosts the Immunomodulatory and Regenerative Activity of Secreted Extracellular Vesicles. Pharmaceutics 2024; 16:1316. [PMID: 39458645 PMCID: PMC11510928 DOI: 10.3390/pharmaceutics16101316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 09/27/2024] [Accepted: 10/07/2024] [Indexed: 10/28/2024] Open
Abstract
Background: Mesenchymal stem cells (MSCs)-derived extracellular vesicles (EVs) have been proposed as an alternative to live-cell administration for Acute Respiratory Distress Syndrome (ARDS). MSC-EVs can be chiefly influenced by the environment to which the MSCs are exposed. Here, lipopolysaccharide (LPS) priming of MSCs was used as a strategy to boost the natural therapeutic potential of the EVs in acute lung injury (ALI). Methods: The regenerative and immunemodulatory effect of LPS-primed MSC-EVs (LPS-EVs) and non-primed MSC-EVs (C-EVs) were evaluated in vitro on alveolar epithelial cells and macrophage-like THP-1 cells. In vivo, ALI was induced in adult male rats by the intrapulmonary instillation of HCl and LPS. Rats (n = 8 to 22/group) were randomized to receive a single bolus (1 × 108 particles) of LPS-EVs, C-EVs, or saline. Lung injury severity was assessed at 72 h in lung tissue and bronchoalveolar lavage. Results: In vitro, LPS-EVs improved wound regeneration and attenuated the inflammatory response triggered by the P. aeruginosa infection, enhancing the M2 macrophage phenotype. In in vivo studies, LPS-EVs, but not C-EVs, significantly decreased the neutrophilic infiltration and myeloperoxidase (MPO) activity in lung tissue. Alveolar macrophages from LPS-EVs-treated animals exhibited a reduced expression of CXCL-1, a key neutrophil chemoattractant. However, both C-EVs and LPS-EVs reduced alveolar epithelial and endothelial permeability, mitigating lung damage. Conclusions: EVs from LPS-primed MSCs resulted in a better resolution of ALI, achieving a greater balance in neutrophil infiltration and activation, while avoiding the complete disruption of the alveolar barrier. This opens new avenues, paving the way for the clinical implementation of cell-based therapies.
Collapse
Affiliation(s)
- Aina Areny-Balagueró
- Critical Care Research Center, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí (I3PT-CERCA), Universitat Autònoma de Barcelona, 08208 Sabadell, Spain; (M.C.-R.); (E.C.-D.); (A.C.); (A.A.)
- Centro de Investigaciones Biomédicas en Red de Enfermedades Respiratorias, CIBERES-Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Marta Camprubí-Rimblas
- Critical Care Research Center, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí (I3PT-CERCA), Universitat Autònoma de Barcelona, 08208 Sabadell, Spain; (M.C.-R.); (E.C.-D.); (A.C.); (A.A.)
- Centro de Investigaciones Biomédicas en Red de Enfermedades Respiratorias, CIBERES-Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Elena Campaña-Duel
- Critical Care Research Center, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí (I3PT-CERCA), Universitat Autònoma de Barcelona, 08208 Sabadell, Spain; (M.C.-R.); (E.C.-D.); (A.C.); (A.A.)
- Centro de Investigaciones Biomédicas en Red de Enfermedades Respiratorias, CIBERES-Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Anna Solé-Porta
- Institut de Ciència de Materials de Barcelona, ICMAB-CSIC, Campus UAB, 08193 Bellaterra, Spain; (A.S.-P.); (A.R.)
| | - Adrián Ceccato
- Critical Care Research Center, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí (I3PT-CERCA), Universitat Autònoma de Barcelona, 08208 Sabadell, Spain; (M.C.-R.); (E.C.-D.); (A.C.); (A.A.)
- Centro de Investigaciones Biomédicas en Red de Enfermedades Respiratorias, CIBERES-Instituto de Salud Carlos III, 28029 Madrid, Spain
- Intensive Care Unit, Hospital Universitari Sagrat Cor, Grupo Quironsalud, 08029 Barcelona, Spain
| | - Anna Roig
- Institut de Ciència de Materials de Barcelona, ICMAB-CSIC, Campus UAB, 08193 Bellaterra, Spain; (A.S.-P.); (A.R.)
| | - John G. Laffey
- REMEDI, CÚRAM Centre for Medical Device Research, University of Galway, H91 TK33 Galway, Ireland;
| | - Daniel Closa
- Institut d’Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (IIBB-CSIC), 08036 Barcelona, Spain;
| | - Antonio Artigas
- Critical Care Research Center, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí (I3PT-CERCA), Universitat Autònoma de Barcelona, 08208 Sabadell, Spain; (M.C.-R.); (E.C.-D.); (A.C.); (A.A.)
- Centro de Investigaciones Biomédicas en Red de Enfermedades Respiratorias, CIBERES-Instituto de Salud Carlos III, 28029 Madrid, Spain
- Servei de Medicina Intensiva, Corporació Sanitària i Universitària Parc Taulí, 08208 Sabadell, Spain
| |
Collapse
|
13
|
Bülow Anderberg S, Huckriede J, Hultström M, Larsson A, de Vries F, Lipcsey M, Nicolaes GAF, Frithiof R. Association of corticosteroid therapy with reduced acute kidney injury and lower NET markers in severe COVID-19: an observational study. Intensive Care Med Exp 2024; 12:85. [PMID: 39340756 PMCID: PMC11438749 DOI: 10.1186/s40635-024-00670-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Accepted: 09/09/2024] [Indexed: 09/30/2024] Open
Abstract
BACKGROUND Acute kidney injury (AKI) is common in critical cases of coronavirus disease 2019 (COVID-19) and associated with worse outcome. Dysregulated neutrophil extracellular trap (NET) formation is one of several suggested pathophysiological mechanisms involved in the development of COVID-19 associated AKI. The corticosteroid dexamethasone was implemented as a standard treatment for severe COVID-19 as of June 2020. A sub-analysis of a prospective observational single center study was performed to evaluate the effect of corticosteroid treatment on AKI development and NET markers in critical cases of COVID-19. RESULTS Two hundred and ten adult patients admitted to intensive care at a tertiary level hospital due to respiratory failure or shock secondary to SARS-CoV-2-infection between March 13th 2020 and January 14th 2021 were included in the study. Ninety-seven of those did not receive corticosteroids. One hundred and thirteen patients were treated with corticosteroids [dexamethasone (n = 98) or equivalent treatment (n = 15)], but the incidence of AKI was assessed only in patients that received corticosteroids before any registered renal dysfunction (n = 63). Corticosteroids were associated with a lower incidence of AKI (19% vs 55.8%, p < 0.001). Fewer patients demonstrated detectable concentrations of extracellular histones in plasma when treated with corticosteroids (8.7% vs 43.1%; p < 0.001). Extracellular histones and in particular non-proteolyzed histones were observed more frequently with increasing AKI severity (p < 0.001). MPO-DNA was found in lower concentrations in patients that received corticosteroids before established renal dysfunction (p = 0.03) and was found in higher concentrations in patients with AKI stage 3 (p = 0.03). Corticosteroids did not ameliorate established AKI during the first week of treatment. CONCLUSION Corticosteroid treatment in severe COVID-19 is associated with a lower incidence of AKI and reduced concentrations of NET markers in plasma.
Collapse
Affiliation(s)
- Sara Bülow Anderberg
- Department of Surgical Sciences, Anesthesiology and Intensive Care, Uppsala University, 751 85, Uppsala, Sweden.
| | - Joram Huckriede
- Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands
| | - Michael Hultström
- Department of Surgical Sciences, Anesthesiology and Intensive Care, Uppsala University, 751 85, Uppsala, Sweden
- Department of Medical Cell Biology, Integrative Physiology, Uppsala University, Uppsala, Sweden
| | - Anders Larsson
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Femke de Vries
- Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands
| | - Miklos Lipcsey
- Department of Surgical Sciences, Anesthesiology and Intensive Care, Uppsala University, 751 85, Uppsala, Sweden
- Hedenstierna Laboratory, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Gerry A F Nicolaes
- Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands
| | - Robert Frithiof
- Department of Surgical Sciences, Anesthesiology and Intensive Care, Uppsala University, 751 85, Uppsala, Sweden
- Uppsala Centre for Paediatric Anesthesia and Intensive Care Research, Uppsala, Sweden
| |
Collapse
|
14
|
Patel H, Carter MJ, Jackson H, Powell O, Fish M, Terranova-Barberio M, Spada F, Petrov N, Wellman P, Darnell S, Mustafa S, Todd K, Bishop C, Cohen JM, Kenny J, van den Berg S, Sun T, Davis F, Jennings A, Timms E, Thomas J, Nyirendra M, Nichols S, Estamiana Elorieta L, D'Souza G, Wright V, De T, Habgood-Coote D, Ramnarayan P, Tissières P, Whittaker E, Herberg J, Cunnington A, Kaforou M, Ellis R, Malim MH, Tibby SM, Shankar-Hari M, Levin M. Shared neutrophil and T cell dysfunction is accompanied by a distinct interferon signature during severe febrile illnesses in children. Nat Commun 2024; 15:8224. [PMID: 39300098 DOI: 10.1038/s41467-024-52246-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 08/22/2024] [Indexed: 09/22/2024] Open
Abstract
Severe febrile illnesses in children encompass life-threatening organ dysfunction caused by diverse pathogens and other severe inflammatory syndromes. A comparative approach to these illnesses may identify shared and distinct features of host immune dysfunction amenable to immunomodulation. Here, using immunophenotyping with mass cytometry and cell stimulation experiments, we illustrate trajectories of immune dysfunction in 74 children with multi-system inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2, 30 with bacterial infection, 16 with viral infection, 8 with Kawasaki disease, and 42 controls. We explore these findings in a secondary cohort of 500 children with these illnesses and 134 controls. We show that neutrophil activation and apoptosis are prominent in multi-system inflammatory syndrome, and that this is partially shared with bacterial infection. We show that memory T cells from patients with multi-system inflammatory syndrome and bacterial infection are exhausted. In contrast, we show viral infection to be characterized by a distinct signature of decreased interferon signaling and lower interferon receptor gene expression. Improved understanding of immune dysfunction may improve approaches to immunomodulator therapy in severe febrile illnesses in children.
Collapse
Affiliation(s)
- Harsita Patel
- Section of Infectious Diseases, Department of Medicine, St Mary's Hospital Campus, Imperial College London, Praed Street, London, UK
| | - Michael J Carter
- Department of Women and Children's Health, School of Life Course and Population Sciences, King's College London, St Thomas' Hospital, Westminster Bridge Road, London, UK
- Paediatric Intensive Care, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, Westminster Bridge Road, London, UK
| | - Heather Jackson
- Section of Infectious Diseases, Department of Medicine, St Mary's Hospital Campus, Imperial College London, Praed Street, London, UK
| | - Oliver Powell
- Section of Infectious Diseases, Department of Medicine, St Mary's Hospital Campus, Imperial College London, Praed Street, London, UK
| | - Matthew Fish
- School of Immunology and Microbial Sciences, King's College London, Guy's Hospital, Great Maze Pond, London, UK
| | - Manuela Terranova-Barberio
- Advanced Cytometry Platform (Flow Core), Research and Development Department at Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital, Great Maze Pond, London, UK
- Flow Cytometry Core, Barts Cancer Centre, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London, UK
| | - Filomena Spada
- Advanced Cytometry Platform (Flow Core), Research and Development Department at Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital, Great Maze Pond, London, UK
| | - Nedyalko Petrov
- Advanced Cytometry Platform (Flow Core), Research and Development Department at Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital, Great Maze Pond, London, UK
| | - Paul Wellman
- Paediatric Intensive Care, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, Westminster Bridge Road, London, UK
| | - Sarah Darnell
- Section of Infectious Diseases, Department of Medicine, St Mary's Hospital Campus, Imperial College London, Praed Street, London, UK
| | - Sobia Mustafa
- Section of Infectious Diseases, Department of Medicine, St Mary's Hospital Campus, Imperial College London, Praed Street, London, UK
| | - Katrina Todd
- Advanced Cytometry Platform (Flow Core), Research and Development Department at Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital, Great Maze Pond, London, UK
| | - Cynthia Bishop
- Advanced Cytometry Platform (Flow Core), Research and Development Department at Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital, Great Maze Pond, London, UK
| | - Jonathan M Cohen
- Paediatric Immunology and Infectious Diseases, Evelina London Children's Hospital, Westminster Bridge Road, London, UK
| | - Julia Kenny
- Paediatric Immunology and Infectious Diseases, Evelina London Children's Hospital, Westminster Bridge Road, London, UK
| | - Sarah van den Berg
- Paediatric Intensive Care, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, Westminster Bridge Road, London, UK
| | - Thomas Sun
- Paediatric Intensive Care, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, Westminster Bridge Road, London, UK
| | - Francesca Davis
- Paediatric Immunology and Infectious Diseases, Evelina London Children's Hospital, Westminster Bridge Road, London, UK
| | - Aislinn Jennings
- Department of Women and Children's Health, School of Life Course and Population Sciences, King's College London, St Thomas' Hospital, Westminster Bridge Road, London, UK
| | - Emma Timms
- School of Immunology and Microbial Sciences, King's College London, Guy's Hospital, Great Maze Pond, London, UK
| | - Jessica Thomas
- Children's Services, Lewisham and Greenwich NHS Foundation Trust, London, UK
| | - Maggie Nyirendra
- Children's Services, Lewisham and Greenwich NHS Foundation Trust, London, UK
| | - Samuel Nichols
- Section of Infectious Diseases, Department of Medicine, St Mary's Hospital Campus, Imperial College London, Praed Street, London, UK
| | - Leire Estamiana Elorieta
- Section of Infectious Diseases, Department of Medicine, St Mary's Hospital Campus, Imperial College London, Praed Street, London, UK
| | - Giselle D'Souza
- Section of Infectious Diseases, Department of Medicine, St Mary's Hospital Campus, Imperial College London, Praed Street, London, UK
| | - Victoria Wright
- Section of Infectious Diseases, Department of Medicine, St Mary's Hospital Campus, Imperial College London, Praed Street, London, UK
| | - Tisham De
- Section of Infectious Diseases, Department of Medicine, St Mary's Hospital Campus, Imperial College London, Praed Street, London, UK
| | - Dominic Habgood-Coote
- Section of Infectious Diseases, Department of Medicine, St Mary's Hospital Campus, Imperial College London, Praed Street, London, UK
| | - Padmanabhan Ramnarayan
- Department of Surgery and Cancer, St Mary's Hospital Campus, Imperial College London, London, UK
| | - Pierre Tissières
- Institut de la Biologie de la cellule, Université Paris Saclay, Gif-sur-Yvette, Departement de l'Essone, Gif-sur-Yvette, France
| | - Elizabeth Whittaker
- Section of Infectious Diseases, Department of Medicine, St Mary's Hospital Campus, Imperial College London, Praed Street, London, UK
| | - Jethro Herberg
- Section of Infectious Diseases, Department of Medicine, St Mary's Hospital Campus, Imperial College London, Praed Street, London, UK
| | - Aubrey Cunnington
- Section of Infectious Diseases, Department of Medicine, St Mary's Hospital Campus, Imperial College London, Praed Street, London, UK
| | - Myrsini Kaforou
- Section of Infectious Diseases, Department of Medicine, St Mary's Hospital Campus, Imperial College London, Praed Street, London, UK
| | - Richard Ellis
- Advanced Cytometry Platform (Flow Core), Research and Development Department at Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital, Great Maze Pond, London, UK
| | - Michael H Malim
- School of Immunology and Microbial Sciences, King's College London, Guy's Hospital, Great Maze Pond, London, UK
| | - Shane M Tibby
- Department of Women and Children's Health, School of Life Course and Population Sciences, King's College London, St Thomas' Hospital, Westminster Bridge Road, London, UK
- Paediatric Intensive Care, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, Westminster Bridge Road, London, UK
| | - Manu Shankar-Hari
- Institute for Regeneration and Repair, Centre for Inflammation Research, University of Edinburgh, Edinburgh Royal Infirmary, Little France Crescent, Edinburgh, UK.
| | - Michael Levin
- Section of Infectious Diseases, Department of Medicine, St Mary's Hospital Campus, Imperial College London, Praed Street, London, UK.
| |
Collapse
|
15
|
Da Silva E, Martín-Cano FE, Gómez-Arrones V, Gaitskell-Phillips G, Alonso JM, Rey J, Becerro L, Gil MC, Peña FJ, Ortega-Ferrusola C. Bacterial endometritis-induced changes in the endometrial proteome in mares: Potential uterine biomarker for bacterial endometritis. Theriogenology 2024; 226:202-212. [PMID: 38909435 DOI: 10.1016/j.theriogenology.2024.06.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Revised: 06/10/2024] [Accepted: 06/12/2024] [Indexed: 06/25/2024]
Abstract
Equine endometritis is one of the main causes of subfertility in the mare. Unraveling the molecular mechanisms involved in this condition and pinpointing proteins with biomarker potential could be crucial in both diagnosing and treating this condition. This study aimed to identify the endometritis-induced changes in the endometrial proteome in mares and to elucidate potential biological processes in which these proteins may be involved. Secondly, biomarkers related to bacterial endometritis (BE) in mares were identified. Uterine lavage fluid samples were collected from 28 mares (14 healthy: negative cytology and culture, and no clinical signs and 14 mares with endometritis: positive cytology and culture, in addition to clinical signs). Proteomic analysis was performed with a UHPLC-MS/MS system and bioinformatic analysis was carried out using Qlucore Omics Explorer. Gene Ontology enrichment and pathway analysis (PANTHER and KEGG) of the uterine proteome were performed to identify active biological pathways in enriched proteins from each group. Quantitative analysis revealed 38 proteins differentially abundant in endometritis mares when compared to healthy mares (fold changes >4.25, and q-value = 0.002). The proteins upregulated in the secretome of mares with BE were involved in biological processes related to the generation of energy and REDOX regulation and to the defense response to bacterium. A total of 24 biomarkers for BE were identified using the biomarker workbench algorithm. Some of the proteins identified were related to the innate immune system such as isoforms of histones H2A and H2B involvement in neutrophil extracellular trap (NET) formation, complement C3a, or gelsolin and profilin, two actin-binding proteins which are essential for dynamic remodeling of the actin cytoskeleton during cell migration. The other group of biomarkers were three known antimicrobial peptides (lysosome, equine cathelicidin 2 and myeloperoxidase (MPO)) and two uncharacterized proteins with a high homology with cathelicidin families. Findings in this study provide the first evidence that innate immune cells in the equine endometrium undergo reprogramming of metabolic pathways similar to the Warburg effect during activation. In addition, biomarkers of BE in uterine fluid of mares including the new proteins identified, as well as other antimicrobial peptides already known, offer future lines of research for alternative treatments to antibiotics.
Collapse
Affiliation(s)
- E Da Silva
- Laboratory of Equine Reproduction and Equine Spermatology, Department of Animal Medicine, Faculty of Veterinary Medicine, University of Extremadura, Cáceres, Spain
| | - F E Martín-Cano
- Laboratory of Equine Reproduction and Equine Spermatology, Department of Animal Medicine, Faculty of Veterinary Medicine, University of Extremadura, Cáceres, Spain
| | - V Gómez-Arrones
- CENSYRA, Centro de Selección y Reproducción Animal de Extremadura, Badajoz, Spain
| | - G Gaitskell-Phillips
- Laboratory of Equine Reproduction and Equine Spermatology, Department of Animal Medicine, Faculty of Veterinary Medicine, University of Extremadura, Cáceres, Spain
| | - J M Alonso
- Unit of Infectious Diseases, University of Extremadura, Caceres, Spain
| | - J Rey
- Unit of Infectious Diseases, University of Extremadura, Caceres, Spain
| | - L Becerro
- Laboratory of Equine Reproduction and Equine Spermatology, Department of Animal Medicine, Faculty of Veterinary Medicine, University of Extremadura, Cáceres, Spain
| | - M C Gil
- Laboratory of Equine Reproduction and Equine Spermatology, Department of Animal Medicine, Faculty of Veterinary Medicine, University of Extremadura, Cáceres, Spain
| | - F J Peña
- Laboratory of Equine Reproduction and Equine Spermatology, Department of Animal Medicine, Faculty of Veterinary Medicine, University of Extremadura, Cáceres, Spain
| | - C Ortega-Ferrusola
- Laboratory of Equine Reproduction and Equine Spermatology, Department of Animal Medicine, Faculty of Veterinary Medicine, University of Extremadura, Cáceres, Spain.
| |
Collapse
|
16
|
Jankowski J, Kozub KO, Kleibert M, Camlet K, Kleibert K, Cudnoch-Jędrzejewska A. The Role of Programmed Types of Cell Death in Pathogenesis of Heart Failure with Preserved Ejection Fraction. Int J Mol Sci 2024; 25:9921. [PMID: 39337409 PMCID: PMC11432194 DOI: 10.3390/ijms25189921] [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: 07/29/2024] [Revised: 09/07/2024] [Accepted: 09/12/2024] [Indexed: 09/30/2024] Open
Abstract
Heart failure with preserved ejection fraction (HFpEF) is a condition that develops in the course of many diseases and conditions, and its pathophysiology is still not well understood, but the involvement of programmed types of cell death in the development of this type of heart failure is becoming increasingly certain. In addition, drugs already widely used in clinical practice, with a good safety profile and efficacy demonstrated in large-group clinical trials, seem to be exerting their beneficial effects on cardiovascular health. Perhaps new drugs that reduce the susceptibility of cells to programmed types of cell death are under investigation and may improve the prognosis of patients with HFpEF. In this article, we summarize the current knowledge about the pathogenesis of HFpEF and the role of programmed types of cell death in its development. Additionally, we have described the future directions of research that may lead to the improvement of a patient's prognosis and potential treatment.
Collapse
Affiliation(s)
- Jan Jankowski
- 1st Chair and Department of Cardiology, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Kamil Oskar Kozub
- Chair and Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, 02-097 Warsaw, Poland
| | - Marcin Kleibert
- Chair and Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, 02-097 Warsaw, Poland
| | - Katarzyna Camlet
- Chair and Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, 02-097 Warsaw, Poland
| | - Klaudia Kleibert
- Department of Pediatric Gastroenterology and Nutrition, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Agnieszka Cudnoch-Jędrzejewska
- Chair and Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, 02-097 Warsaw, Poland
| |
Collapse
|
17
|
Dumont BL, Neagoe PE, Charles E, Villeneuve L, Ninni S, Tardif JC, Räkel A, White M, Sirois MG. Low-Density Neutrophils and Neutrophil Extracellular Traps (NETs) Are New Inflammatory Players in Heart Failure. Can J Cardiol 2024; 40:1524-1535. [PMID: 38555028 DOI: 10.1016/j.cjca.2024.03.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 03/11/2024] [Accepted: 03/22/2024] [Indexed: 04/02/2024] Open
Abstract
BACKGROUND Heart failure with reduced (HFrEF) or preserved ejection fraction (HFpEF) is characterized by low-grade chronic inflammation. Circulating neutrophils regroup 2 subtypes termed high- and low-density neutrophils (HDNs and LDNs). LDNs represent less than 2% of total neutrophil under physiological conditions, but their counts increase in multiple pathologies, releasing more inflammatory cytokines and neutrophil extracellular traps (NETs). The aims of this study were to assess the differential count and role of HDNs, LDNs, and NETs-related activities in patients with heart failure (HF). METHODS HDNs and LDNs were isolated from human blood by density gradient and purified by fluorescence-activated cell sorting (FACS) and their counts obtained by flow cytometry. Formation of NETs (NETosis) was quantified by confocal microscopy. Circulating inflammatory and NETosis biomarkers were measured by enzyme-linked immunosorbent assay (ELISA). Neutrophil adhesion onto human extracellular matrix (hECM) was assessed by optical microscopy. RESULTS A total of 140 individuals were enrolled, including 33 healthy volunteers (HVs), 41 HFrEF (19 stable patients and 22 presenting acute decompensated HF [ADHF]), and 66 patients with HFpEF (36 stable patients and 30 presenting HF decompensation). HDNs and LDNs counts were significantly increased up to 39% and 2740%, respectively, in patients with HF compared with HVs. In patients with HF, the correlations among LDNs counts and circulating inflammatory (CRP, IL-6 and -8), troponin T, N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and NETosis components were significant. In vitro, LDNs expressed more citrullinated histone H3 (H3Cit) and NETs and were more proadhesive, with ADHFpEF patients presenting the highest proinflammatory profile. CONCLUSIONS Patients with HFpEF present higher levels of circulating LDNs- and NETs-related activities, which are the highest in the context of acute HF decompensation.
Collapse
Affiliation(s)
- Benjamin L Dumont
- Research Center, Montreal Heart Institute, Montréal, Québec, Canada; Departments of Pharmacology and Physiology, Université de Montréal, Montréal, Québec, Canada
| | | | - Elcha Charles
- Research Center, Montreal Heart Institute, Montréal, Québec, Canada; Departments of Pharmacology and Physiology, Université de Montréal, Montréal, Québec, Canada
| | - Louis Villeneuve
- Research Center, Montreal Heart Institute, Montréal, Québec, Canada
| | - Sandro Ninni
- Research Center, Montreal Heart Institute, Montréal, Québec, Canada; CHU Lille, Institut Coeur Poumon, Université de Lille, Lille, France
| | - Jean-Claude Tardif
- Research Center, Montreal Heart Institute, Montréal, Québec, Canada; Department of Medicine, Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada
| | - Agnès Räkel
- Research Center, Centre Hospitalier de l'Université de Montréal (CHUM), Montréal, Québec, Canada; Department of Medicine, Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada
| | - Michel White
- Research Center, Montreal Heart Institute, Montréal, Québec, Canada; Department of Medicine, Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada
| | - Martin G Sirois
- Research Center, Montreal Heart Institute, Montréal, Québec, Canada; Departments of Pharmacology and Physiology, Université de Montréal, Montréal, Québec, Canada.
| |
Collapse
|
18
|
Li Y, Yang T, Jiang B. Neutrophil and neutrophil extracellular trap involvement in neutrophilic asthma: A review. Medicine (Baltimore) 2024; 103:e39342. [PMID: 39183388 PMCID: PMC11346896 DOI: 10.1097/md.0000000000039342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 03/21/2024] [Accepted: 07/26/2024] [Indexed: 08/27/2024] Open
Abstract
Asthma is a highly prevalent chronic inflammatory disease characterized by variable airflow obstruction and airway hyperresponsiveness. Neutrophilic asthma (NA) is classified as "type 2 low" asthma, defined as 65% or more neutrophils in the total cell count. There is no clear consensus on the pathogenesis of NA, and the accumulation of neutrophils and release of neutrophil extracellular traps (NETs) may be responsible for its development. A NET is a large extracellular meshwork comprising cell membrane and granule proteins. It is a powerful antimicrobial defence system that traps, neutralizes, and kills bacteria, fungi, viruses, and parasites and prevents the spread of microorganisms. However, dysregulation of NETs may lead to chronic airway inflammation, is associated with worsening of asthma, and has been the subject of major research advances in chronic lung diseases in recent years. NA is insensitive to steroids, and there is a need to find effective biomarkers as targets for the treatment of NA to replace steroids. This review analyses the mechanisms of action between asthmatic neutrophil recruitment and NET formation and their impact on NA development. It also discusses their possible therapeutic significance in NA, summarizing the advances made in NA agents and providing strategies for the treatment of NA, provide a theoretical basis for the development of new therapeutic drugs, thereby improving the level of diagnosis and treatment, and promoting the research progress in the field of asthma.
Collapse
Affiliation(s)
- Yuemu Li
- Institutes of Integrative Medicine, Heilongjiang Provincial Hospital of Traditional Chinese Medicine, Heilongjiang, China
| | - Tianyi Yang
- Institutes of Integrative Medicine, Heilongjiang Provincial Hospital of Traditional Chinese Medicine, Heilongjiang, China
| | - Baihua Jiang
- Institutes of Integrative Medicine, Heilongjiang Provincial Hospital of Traditional Chinese Medicine, Heilongjiang, China
| |
Collapse
|
19
|
Ma Y, Wei J, He W, Ren J. Neutrophil extracellular traps in cancer. MedComm (Beijing) 2024; 5:e647. [PMID: 39015554 PMCID: PMC11247337 DOI: 10.1002/mco2.647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 06/11/2024] [Accepted: 06/12/2024] [Indexed: 07/18/2024] Open
Abstract
Neutrophil extracellular traps (NETs), which consist of chromatin DNA studded with granule proteins, are released by neutrophils in response to both infectious and sterile inflammation. Beyond the canonical role in defense against pathogens, the extrusion of NETs also contributes to the initiation, metastasis, and therapeutic response of malignant diseases. Recently, NETs have been implicated in the development and therapeutic responses of various types of tumors. Although extensive work regarding inflammation in tumors has been reported, a comprehensive summary of how these web-like extracellular structures initiate and propagate tumor progression under the specific microenvironment is lacking. In this review, we demonstrate the initiators and related signaling pathways that trigger NETs formation in cancers. Additionally, this review will outline the current molecular mechanisms and regulatory networks of NETs during dormant cancer cells awakening, circulating tumor cells (CTCs) extravasation, and metastatic recurrence of cancer. This is followed by a perspective on the current and potential clinical potential of NETs as therapeutic targets in the treatment of both local and metastatic disease, including the improvement of the efficacy of existing therapies.
Collapse
Affiliation(s)
- Yuxi Ma
- Cancer CenterUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Institute of Radiation OncologyUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Hubei Key Laboratory of Precision Radiation OncologyWuhanChina
| | - Jielin Wei
- Cancer CenterUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Institute of Radiation OncologyUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Hubei Key Laboratory of Precision Radiation OncologyWuhanChina
| | - Wenshan He
- Department of Breast and Thyroid SurgeryUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Jinghua Ren
- Cancer CenterUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Institute of Radiation OncologyUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Hubei Key Laboratory of Precision Radiation OncologyWuhanChina
| |
Collapse
|
20
|
Delinois LJ, Sharma A, Ramesh AK, Boatright LD, Li Q, Xu R, Luo HR, Mishra BB, Sharma J. Poly(ADP-Ribose) Polymerase-1 Regulates Pyroptosis Independent Function of NLRP3 Inflammasome in Neutrophil Extracellular Trap Formation. Immunohorizons 2024; 8:586-597. [PMID: 39186692 PMCID: PMC11374751 DOI: 10.4049/immunohorizons.2400058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 07/24/2024] [Indexed: 08/28/2024] Open
Abstract
Neutrophil extracellular traps (NETs) function to control infectious agents as well as to propagate inflammatory response in a variety of disease conditions. DNA damage associated with chromatin decondensation and NACHT domain-leucine-rich repeat-and pyrin domain-containing protein 3 (NLRP3) inflammasome activation have emerged as crucial events in NET formation, but the link between the two processes is unknown. In this study, we demonstrate that poly(ADP-ribose) polymerase-1 (PARP-1), a key DNA repair enzyme, regulates NET formation triggered by NLRP3 inflammasome activation in neutrophils. Activation of mouse neutrophils with canonical NLRP3 stimulants LPS and nigericin induced NET formation, which was significantly abrogated by pharmacological inhibition of PARP-1. We found that PARP-1 is required for NLRP3 inflammasome assembly by regulating post-transcriptional levels of NLRP3 and ASC dimerization. Importantly, this PARP-1-regulated NLRP3 activation for NET formation was independent of inflammasome-mediated pyroptosis, because caspase-1 and gasdermin D processing as well as IL-1β transcription and secretion remained intact upon PARP-1 inhibition in neutrophils. Accordingly, pharmacological inhibition or genetic ablation of caspase-1 and gasdermin D had no effect on NLRP3-mediated NET formation. Mechanistically, PARP-1 inhibition increased p38 MAPK activity, which was required for downmodulation of NLRP3 and NETs, because concomitant inhibition of p38 MAPK with PARP-1 restored NLRP3 activation and NET formation. Finally, mice undergoing bacterial peritonitis exhibited increased survival upon treatment with PARP-1 inhibitor, which correlated with increased leukocyte influx and improved intracellular bacterial clearance. Our findings reveal a noncanonical pyroptosis-independent role of NLRP3 in NET formation regulated by PARP-1 via p38 MAPK, which can be targeted to control NETosis in inflammatory diseases.
Collapse
Affiliation(s)
- Louis J. Delinois
- Division of Anesthesiology, Critical Care & Pain Medicine, Department of Critical Care, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Atul Sharma
- Division of Anesthesiology, Critical Care & Pain Medicine, Department of Critical Care, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Ashwin K. Ramesh
- Division of Anesthesiology, Critical Care & Pain Medicine, Department of Critical Care, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Laurel D. Boatright
- Division of Anesthesiology, Critical Care & Pain Medicine, Department of Critical Care, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Qun Li
- Developmental Dentistry, UT Health Science Center at San Antonio, San Antonio, TX
| | - Rong Xu
- Pathology and Lab Medicine, Boston Children’s Hospital, Boston, MA
| | - Hongbo R. Luo
- Pathology and Lab Medicine, Boston Children’s Hospital, Boston, MA
| | - Bibhuti B. Mishra
- Developmental Dentistry, UT Health Science Center at San Antonio, San Antonio, TX
| | - Jyotika Sharma
- Division of Anesthesiology, Critical Care & Pain Medicine, Department of Critical Care, University of Texas MD Anderson Cancer Center, Houston, TX
| |
Collapse
|
21
|
Wang J, Wang Y, Li J, Ying J, Mu Y, Zhang X, Zhou X, Sun L, Jiang H, Zhuo W, Shen Y, Zhou T, Liu X, Zhou Q. Neutrophil Extracellular Traps-Inhibiting and Fouling-Resistant Polysulfoxides Potently Prevent Postoperative Adhesion, Tumor Recurrence, and Metastasis. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2400894. [PMID: 38636448 DOI: 10.1002/adma.202400894] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 03/19/2024] [Indexed: 04/20/2024]
Abstract
Peritoneal metastasis (PM) is considered one of the most dreaded forms of cancer metastases for both patients and physicians. Aggressive cytoreductive surgery (CRS) is the primary treatment for peritoneal metastasis. Unfortunately, this intensive treatment frequently causes clinical complications, such as postoperative recurrence, metastasis, and adhesion formation. Emerging evidence suggests that neutrophil extracellular traps (NETs) released by inflammatory neutrophils contribute to these complications. Effective NET-targeting strategies thus show considerable potential in counteracting these complications but remain challenging. Here, one type of sulfoxide-containing homopolymer, PMeSEA, with potent fouling-resistant and NET-inhibiting capabilities, is synthesized and screened. Hydrating sulfoxide groups endow PMeSEA with superior nonfouling ability, significantly inhibiting protein/cell adhesion. Besides, the polysulfoxides can be selectively oxidized by ClO- which is required to stabilize the NETs rather than H2O2, and ClO- scavenging effectively inhibits NETs formation without disturbing redox homeostasis in tumor cells and quiescent neutrophils. As a result, PMeSEA potently prevents postoperative adhesions, significantly suppresses peritoneal metastasis, and shows synergetic antitumor activity with chemotherapeutic 5-Fluorouracil. Moreover, coupling CRS with PMeSEA potently inhibits CRS-induced tumor metastatic relapse and postoperative adhesions. Notably, PMeSEA exhibits low in vivo acute and subacute toxicities, implying significant potential for clinical postoperative adjuvant treatment.
Collapse
Affiliation(s)
- Jiafeng Wang
- Department of Pharmacology, and Department of Gastroenterology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China
- Department of Cell Biology, and Department of Gastroenterology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China
- Zhejiang Key Laboratory of Smart Biomaterials and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Yechun Wang
- Department of Cell Biology, and Department of Gastroenterology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China
| | - Junjun Li
- Department of Cell Biology, and Department of Gastroenterology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China
| | - Jiajia Ying
- Department of Cell Biology, and Department of Gastroenterology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China
| | - Yongli Mu
- Department of Cell Biology, and Department of Gastroenterology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China
| | - Xuanhao Zhang
- Department of Cell Biology, and Department of Gastroenterology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China
| | - Xuefei Zhou
- Department of Cell Biology, and Department of Gastroenterology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China
| | - Leimin Sun
- Department of Cell Biology, and Department of Gastroenterology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China
| | - Haiping Jiang
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, China
| | - Wei Zhuo
- Department of Cell Biology, and Department of Gastroenterology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China
- Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310020, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310000, China
| | - Youqing Shen
- Zhejiang Key Laboratory of Smart Biomaterials and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Tianhua Zhou
- Department of Cell Biology, and Department of Gastroenterology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China
- Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310020, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310000, China
| | - Xiangrui Liu
- Department of Pharmacology, and Department of Gastroenterology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China
- Zhejiang Key Laboratory of Smart Biomaterials and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, Zhejiang, 310058, China
- Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310020, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310000, China
| | - Quan Zhou
- Department of Cell Biology, and Department of Gastroenterology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China
- Zhejiang Key Laboratory of Smart Biomaterials and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| |
Collapse
|
22
|
Mousset A, Bellone L, Gaggioli C, Albrengues J. NETscape or NEThance: tailoring anti-cancer therapy. Trends Cancer 2024; 10:655-667. [PMID: 38664080 DOI: 10.1016/j.trecan.2024.03.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 03/14/2024] [Accepted: 03/15/2024] [Indexed: 07/12/2024]
Abstract
Neutrophils, major regulators of innate immunity, have recently emerged as key components of the tumor microenvironment. The role of neutrophils in cancer has been linked to their ability to form neutrophil extracellular traps (NETs), structures composed of decondensed DNA decorated with enzymes that are released into the extracellular space. Here, we discuss the pivotal roles of NETs in influencing responses to anticancer therapies such as chemotherapy, radiotherapy, immunotherapy, and targeted therapy. Highlighting recent insights, we delve into the dual nature of NETs in the context of anticancer treatments, examining their potential to either counteract or enhance treatment outcomes. Strategic targeting of NETs may be a promising avenue for crafting combination therapies to counteract resistance or enhance anticancer treatments' efficacy.
Collapse
Affiliation(s)
- Alexandra Mousset
- University Côte d'Azur, CNRS UMR7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), Nice, France
| | - Lola Bellone
- University Côte d'Azur, CNRS UMR7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), Nice, France
| | - Cedric Gaggioli
- University Côte d'Azur, CNRS UMR7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), Nice, France
| | - Jean Albrengues
- University Côte d'Azur, CNRS UMR7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), Nice, France.
| |
Collapse
|
23
|
Harman RM, Sipka A, Oxford KA, Oliveira L, Huntimer L, Nydam DV, Van de Walle GR. The mammosphere-derived epithelial cell secretome modulates neutrophil functions in the bovine model. Front Immunol 2024; 15:1367432. [PMID: 38994364 PMCID: PMC11236729 DOI: 10.3389/fimmu.2024.1367432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 06/17/2024] [Indexed: 07/13/2024] Open
Abstract
Background Innovative therapies against bacterial infections are needed. One approach is to focus on host-directed immunotherapy (HDT), with treatments that exploit natural processes of the host immune system. The goals of this type of therapy are to stimulate protective immunity while minimizing inflammation-induced tissue damage. We use non-traditional large animal models to explore the potential of the mammosphere-derived epithelial cell (MDEC) secretome, consisting of all bioactive factors released by the cells, to modulate host immune functions. MDEC cultures are enriched for mammary stem and progenitor cells and can be generated from virtually any mammal. We previously demonstrated that the bovine MDEC secretome, collected and delivered as conditioned medium (CM), inhibits the growth of bacteria in vitro and stimulates functions related to tissue repair in cultured endothelial and epithelial cells. Methods The immunomodulatory effects of the bovine MDEC secretome on bovine neutrophils, an innate immune cell type critical for resolving bacterial infections, were determined in vitro using functional assays. The effects of MDEC CM on neutrophil molecular pathways were explored by evaluating the production of specific cytokines by neutrophils and examining global gene expression patterns in MDEC CM-treated neutrophils. Enzyme linked immunosorbent assays were used to determine the concentrations of select proteins in MDEC CM and siRNAs were used to reduce the expression of specific MDEC-secreted proteins, allowing for the identification of bioactive factors modulating neutrophil functions. Results Neutrophils exposed to MDEC secretome exhibited increased chemotaxis and phagocytosis and decreased intracellular reactive oxygen species and extracellular trap formation, when compared to neutrophils exposed to control medium. C-X-C motif chemokine 6, superoxide dismutase, peroxiredoxin-2, and catalase, each present in the bovine MDEC secretome, were found to modulate neutrophil functions. Conclusion The MDEC secretome administered to treat bacterial infections may increase neutrophil recruitment to the site of infection, stimulate pathogen phagocytosis by neutrophils, and reduce neutrophil-produced ROS accumulation. As a result, pathogen clearance might be improved and local inflammation and tissue damage reduced.
Collapse
Affiliation(s)
- Rebecca M. Harman
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States
| | - Anja Sipka
- Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States
| | - Kelly A. Oxford
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States
| | | | | | - Daryl V. Nydam
- Department of Public and Ecosystem Health, Cornell University, Ithaca, NY, United States
| | - Gerlinde R. Van de Walle
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States
| |
Collapse
|
24
|
Gao G, Liu R, Wu D, Gao D, Lv Y, Xu X, Fu B, Lin Z, Wang T, He A, Bai J. Risk score constructed with neutrophil extracellular traps-related genes predicts prognosis and immune microenvironment in multiple myeloma. Front Oncol 2024; 14:1365460. [PMID: 38919521 PMCID: PMC11196624 DOI: 10.3389/fonc.2024.1365460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 05/28/2024] [Indexed: 06/27/2024] Open
Abstract
Background Multiple myeloma (MM) exhibits considerable heterogeneity in treatment responses and survival rates, even when standardized care is administered. Ongoing efforts are focused on developing prognostic models to predict these outcomes more accurately. Recently, neutrophil extracellular traps (NETs) have emerged as a potential factor in MM progression, sparking investigation into their role in prognostication. Methods In this study, a multi-gene risk scoring model was constructed using the intersection of NTEs and differentially expressed genes (DEGs), applying the least absolute shrinkage and selection operator (LASSO) Cox regression model. A nomogram was established, and the prognostic model's effectiveness was determined via Kaplan-Meier survival analysis, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA). The ESTIMATE algorithm and immune-related single-sample gene set enrichment analysis (ssGSEA) were employed to evaluate the level of immune infiltration. The sensitivity of chemotherapy drugs was assessed using the Genomics of Drug Sensitivity in Cancer (GDSC) database. Ultimately, the presence of the detected genes was confirmed through quantitative real-time polymerase chain reaction (qRT-PCR) analysis in MM cell specimens. Results 64 NETs-DEGs were yielded, and through univariate Cox regression and LASSO regression analysis, we constructed a risk score composed of six genes: CTSG, HSPE1, LDHA, MPO, PINK1, and VCAM1. MM patients in three independent datasets were classified into high- and low-risk groups according to the risk score. The overall survival (OS) of patients in the high-risk group was significantly reduced compared to the low-risk group. Furthermore, the risk score was an independent predictive factor for OS. In addition, interactions between the risk score, immune score, and immune cell infiltration were investigated. Further analysis indicated that patients in the high-risk group were more sensitive to a variety of chemotherapy and targeted drugs, including bortezomib. Moreover, the six genes provided insights into the progression of plasma cell disorders. Conclusion This study offers novel insights into the roles of NETs in prognostic prediction, immune status, and drug sensitivity in MM, serving as a valuable supplement and enhancement to existing grading systems.
Collapse
Affiliation(s)
- Gongzhizi Gao
- Department of Hematology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Rui Liu
- Department of Hematology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Dong Wu
- Department of Hematology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Dandan Gao
- Department of Hematology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Yang Lv
- Department of Hematology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Xuezhu Xu
- Department of Hematology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Bingjie Fu
- Department of Hematology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Zujie Lin
- Department of Hematology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Ting Wang
- Department of Hematology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Aili He
- Department of Hematology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- National-Local Joint Engineering Research Center of Biodiagnostics & Biotherapy, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Xi’an Key Laboratory of hematological diseases, Xi’an, China
| | - Ju Bai
- Department of Hematology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Xi’an Key Laboratory of hematological diseases, Xi’an, China
| |
Collapse
|
25
|
Wu Y, Wang L, Li Y, Cao Y, Wang M, Deng Z, Kang H. Immunotherapy in the context of sepsis-induced immunological dysregulation. Front Immunol 2024; 15:1391395. [PMID: 38835773 PMCID: PMC11148279 DOI: 10.3389/fimmu.2024.1391395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Accepted: 05/06/2024] [Indexed: 06/06/2024] Open
Abstract
Sepsis is a clinical syndrome caused by uncontrollable immune dysregulation triggered by pathogen infection, characterized by high incidence, mortality rates, and disease burden. Current treatments primarily focus on symptomatic relief, lacking specific therapeutic interventions. The core mechanism of sepsis is believed to be an imbalance in the host's immune response, characterized by early excessive inflammation followed by late immune suppression, triggered by pathogen invasion. This suggests that we can develop immunotherapeutic treatment strategies by targeting and modulating the components and immunological functions of the host's innate and adaptive immune systems. Therefore, this paper reviews the mechanisms of immune dysregulation in sepsis and, based on this foundation, discusses the current state of immunotherapy applications in sepsis animal models and clinical trials.
Collapse
Affiliation(s)
- Yiqi Wu
- Department of Critical Care Medicine, The First Medical Center, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- Graduate School of The People’s Liberation Army (PLA) General Hospital, Beijing, China
| | - Lu Wang
- Department of Critical Care Medicine, The First Medical Center, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- Graduate School of The People’s Liberation Army (PLA) General Hospital, Beijing, China
| | - Yun Li
- Department of Critical Care Medicine, The First Medical Center, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- Graduate School of The People’s Liberation Army (PLA) General Hospital, Beijing, China
| | - Yuan Cao
- Department of Emergency Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Min Wang
- Department of Critical Care Medicine, The First Medical Center, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- Graduate School of The People’s Liberation Army (PLA) General Hospital, Beijing, China
| | - Zihui Deng
- Department of Basic Medicine, Graduate School, Chinese PLA General Hospital, Beijing, China
| | - Hongjun Kang
- Department of Critical Care Medicine, The First Medical Center, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- National Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, China
| |
Collapse
|
26
|
Park JE, Kim DH. Advanced Immunomodulatory Biomaterials for Therapeutic Applications. Adv Healthc Mater 2024:e2304496. [PMID: 38716543 DOI: 10.1002/adhm.202304496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Revised: 04/15/2024] [Indexed: 05/22/2024]
Abstract
The multifaceted biological defense system modulating complex immune responses against pathogens and foreign materials plays a critical role in tissue homeostasis and disease progression. Recently developed biomaterials that can specifically regulate immune responses, nanoparticles, graphene, and functional hydrogels have contributed to the advancement of tissue engineering as well as disease treatment. The interaction between innate and adaptive immunity, collectively determining immune responses, can be regulated by mechanobiological recognition and adaptation of immune cells to the extracellular microenvironment. Therefore, applying immunomodulation to tissue regeneration and cancer therapy involves manipulating the properties of biomaterials by tailoring their composition in the context of the immune system. This review provides a comprehensive overview of how the physicochemical attributes of biomaterials determine immune responses, focusing on the physical properties that influence innate and adaptive immunity. This review also underscores the critical aspect of biomaterial-based immune engineering for the development of novel therapeutics and emphasizes the importance of understanding the biomaterials-mediated immunological mechanisms and their role in modulating the immune system.
Collapse
Affiliation(s)
- Ji-Eun Park
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, 02841, Republic of Korea
| | - Dong-Hwee Kim
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, 02841, Republic of Korea
- Department of Integrative Energy Engineering, College of Engineering, Korea University, Seoul, 02841, Republic of Korea
- Biomedical Research Center, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea
| |
Collapse
|
27
|
King PT, Dousha L. Neutrophil Extracellular Traps and Respiratory Disease. J Clin Med 2024; 13:2390. [PMID: 38673662 PMCID: PMC11051312 DOI: 10.3390/jcm13082390] [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: 02/28/2024] [Revised: 03/26/2024] [Accepted: 04/17/2024] [Indexed: 04/28/2024] Open
Abstract
Extracellular traps made by neutrophils (NETs) and other leukocytes such as macrophages and eosinophils have a key role in the initial immune response to infection but are highly inflammatory and may contribute to tissue damage. They are particularly relevant to lung disease, with the pulmonary anatomy facilitating their ability to fully extend into the airways/alveolar space. There has been a rapid expansion in the number of published studies demonstrating their role in a variety of important respiratory diseases including chronic obstructive pulmonary disease, cystic fibrosis, bronchiectasis, asthma, pneumonia, COVID-19, rhinosinusitis, interstitial lung disease and lung cancer. The expression of NETs and other traps is a specific process, and diagnostic tests need to differentiate them from other inflammatory pathways/causes of cell death that are also characterised by the presence of extracellular DNA. The specific targeting of this pathway by relevant therapeutics may have significant clinical benefit; however, current clinical trials/evidence are at a very early stage. This review will provide a broad overview of the role of NETs and their possible treatment in respiratory disease.
Collapse
Affiliation(s)
- Paul T. King
- Monash Lung, Sleep, Allergy and Immunology, Monash Medical Centre, 246 Clayton Rd, Clayton, Melbourne, VIC 3168, Australia;
- Department of Medicine, Monash University, Clayton, Melbourne, VIC 3168, Australia
| | - Lovisa Dousha
- Monash Lung, Sleep, Allergy and Immunology, Monash Medical Centre, 246 Clayton Rd, Clayton, Melbourne, VIC 3168, Australia;
- Department of Medicine, Monash University, Clayton, Melbourne, VIC 3168, Australia
| |
Collapse
|
28
|
Birkemeier M, Swindle A, Bowman J, Lynch VJ. Pervasive loss of regulated necrotic cell death genes in elephants, hyraxes, and sea cows ( Paenungualta). BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.04.04.588129. [PMID: 38617256 PMCID: PMC11014510 DOI: 10.1101/2024.04.04.588129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/16/2024]
Abstract
Gene loss can promote phenotypic differences between species, for example, if a gene constrains phenotypic variation in a trait, its loss allows for the evolution of a greater range of variation or even new phenotypes. Here, we explore the contribution of gene loss to the evolution of large bodies and augmented cancer resistance in elephants. We used genomes from 17 Afrotherian and Xenarthran species to identify lost genes, i.e., genes that have pseudogenized or been completely lost, and Dollo parsimony to reconstruct the evolutionary history of gene loss across species. We unexpectedly discovered a burst of gene losses in the Afrotherian stem lineage and found that the loss of genes with functions in regulated necrotic cell death modes was pervasive in elephants, hyraxes, and sea cows (Paenungulata). Among the lost genes are MLKL and RIPK3, which mediate necroptosis, and sensors that activate inflammasomes to induce pyroptosis, including AIM2, MEFV, NLRC4, NLRP1, and NLRP6. These data suggest that the mechanisms that regulate necrosis and pyroptosis are either extremely derived or potentially lost in these lineages, which may contribute to the repeated evolution of large bodies and cancer resistance in Paenungulates as well as susceptibility to pathogen infection.
Collapse
Affiliation(s)
- Meaghan Birkemeier
- Department of Biological Sciences, University at Buffalo, SUNY, 551 Cooke Hall, Buffalo, NY, USA
| | - Arianna Swindle
- Department of Biological Sciences, University at Buffalo, SUNY, 551 Cooke Hall, Buffalo, NY, USA
| | - Jacob Bowman
- Department of Biological Sciences, University at Buffalo, SUNY, 551 Cooke Hall, Buffalo, NY, USA
| | - Vincent J. Lynch
- Department of Biological Sciences, University at Buffalo, SUNY, 551 Cooke Hall, Buffalo, NY, USA
| |
Collapse
|
29
|
Ibrahim N, Eilenberg W, Neumayer C, Brostjan C. Neutrophil Extracellular Traps in Cardiovascular and Aortic Disease: A Narrative Review on Molecular Mechanisms and Therapeutic Targeting. Int J Mol Sci 2024; 25:3983. [PMID: 38612791 PMCID: PMC11012109 DOI: 10.3390/ijms25073983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 03/25/2024] [Accepted: 03/28/2024] [Indexed: 04/14/2024] Open
Abstract
Neutrophil extracellular traps (NETs), composed of DNA, histones, and antimicrobial proteins, are released by neutrophils in response to pathogens but are also recognized for their involvement in a range of pathological processes, including autoimmune diseases, cancer, and cardiovascular diseases. This review explores the intricate roles of NETs in different cardiovascular conditions such as thrombosis, atherosclerosis, myocardial infarction, COVID-19, and particularly in the pathogenesis of abdominal aortic aneurysms. We elucidate the mechanisms underlying NET formation and function, provide a foundational understanding of their biological significance, and highlight the contribution of NETs to inflammation, thrombosis, and tissue remodeling in vascular disease. Therapeutic strategies for preventing NET release are compared with approaches targeting components of formed NETs in cardiovascular disease. Current limitations and potential avenues for clinical translation of anti-NET treatments are discussed.
Collapse
Affiliation(s)
| | | | | | - Christine Brostjan
- Division of Vascular Surgery, Department of General Surgery, Medical University of Vienna, University Hospital Vienna, 1090 Vienna, Austria; (N.I.); (W.E.); (C.N.)
| |
Collapse
|
30
|
Storms N, de la Rebière G, Franck T, Mouithys Mickalad A, Sandersen C, Ceusters J, Serteyn D. Neutrophil extracellular traps and active myeloperoxidase concentrate in lamellar tissue of equids with naturally occurring laminitis. Vet Immunol Immunopathol 2024; 270:110738. [PMID: 38452577 DOI: 10.1016/j.vetimm.2024.110738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 02/20/2024] [Accepted: 02/21/2024] [Indexed: 03/09/2024]
Abstract
Laminitis is a pathology of the equine digit ultimately leading to a failure of the dermo-epidermal interface. Neutrophil activation is recognized as a major factor in SIRS-associated laminitis and has recently been described in induced endocrinopathic laminitis evidenced by the presence of myeloperoxidase (MPO). Neutrophil extracellular traps (NET) are released with neutrophil activation. This study aimed to investigate the presence and activity of MPO and NET in the lamellar tissue of equids presented with naturally occurring laminitis. Samples of lamellar tissue of five horses and five donkeys presented with laminitis, as well as eight control horses without laminitis, were collected. Lamellar tissue extracts were submitted to ELISA and specific immuno-extraction followed by enzymatic detection (SIEFED) assays to confirm the presence and activity of both MPO and NET. Lamellar sections were also immunohistopathologically stained for MPO and NET. Analysis of lamellar tissue extracts revealed that laminitis cases had significantly higher levels of total MPO concentration, MPO activity, and NET-bound MPO activity in comparison to control horses. Moreover, a strong correlation was identified between the activity of NET-bound MPO and the total MPO activity, which suggests that MPO activity partly originates from NET-bound MPO. Immunohistochemical staining showed that MPO and NET labelling in laminitis cases was moderate to marked, primarily in the epidermis and in inflammatory infiltrates containing neutrophils, while labelling in control horses was minimal. This article constitutes the first indication of the presence and activity of NET-bound MPO in the lamellar tissue of horses and donkeys with naturally occurring laminitis. Targeting these substances may provide new treatment possibilities for this debilitating disease.
Collapse
Affiliation(s)
- Nazaré Storms
- Department of Equine Surgery and Anesthesiology of the University of Liège, B41, Quartier vallée 2, Avenue de Cureghem 5D, Liège 4000, Belgium; Center for Oxygen Research and Development, B6, Quartier Agora, B6a, Liège 4000, Belgium.
| | - Geoffroy de la Rebière
- Department of Equine Surgery and Anesthesiology of the University of Liège, B41, Quartier vallée 2, Avenue de Cureghem 5D, Liège 4000, Belgium
| | - Thierry Franck
- Center for Oxygen Research and Development, B6, Quartier Agora, B6a, Liège 4000, Belgium
| | - Ange Mouithys Mickalad
- Center for Oxygen Research and Development, B6, Quartier Agora, B6a, Liège 4000, Belgium
| | - Charlotte Sandersen
- Department of Equine Surgery and Anesthesiology of the University of Liège, B41, Quartier vallée 2, Avenue de Cureghem 5D, Liège 4000, Belgium; Center for Oxygen Research and Development, B6, Quartier Agora, B6a, Liège 4000, Belgium
| | - Justine Ceusters
- Center for Oxygen Research and Development, B6, Quartier Agora, B6a, Liège 4000, Belgium
| | - Didier Serteyn
- Department of Equine Surgery and Anesthesiology of the University of Liège, B41, Quartier vallée 2, Avenue de Cureghem 5D, Liège 4000, Belgium; Center for Oxygen Research and Development, B6, Quartier Agora, B6a, Liège 4000, Belgium
| |
Collapse
|
31
|
Yiu JYT, Hally KE, Larsen PD, Holley AS. Neutrophil-Enriched Biomarkers and Long-Term Prognosis in Acute Coronary Syndrome: a Systematic Review and Meta-analysis. J Cardiovasc Transl Res 2024; 17:426-447. [PMID: 37594719 PMCID: PMC11052791 DOI: 10.1007/s12265-023-10425-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 08/02/2023] [Indexed: 08/19/2023]
Abstract
Activated neutrophils release a range of inflammatory products that represent potential biomarkers, and there is interest in the prognostic value of these in acute coronary syndrome (ACS) patients. We conducted a systematic review to examine neutrophil-enriched biomarkers and the occurrence of major adverse cardiovascular events (MACE) in patients with ACS. We identified twenty-seven studies including 17,831 patients with ACS. The most studied biomarkers were neutrophil gelatinase-associated lipocalin (NGAL) and myeloperoxidase (MPO). Meta-analyses showed that elevated NGAL was associated with higher MACE rates (unadjusted risk ratio (RR) 1.52, 95% CI 1.12-2.06, p = 0.006) as were elevated MPO levels (unadjusted RR 1.61, 95% CI 1.22-2.13, p = 0.01). There was limited data suggesting that increased levels of calprotectin, proteinase-3 and double-stranded DNA were also associated with MACE. These results suggest that higher levels of neutrophil-enriched biomarkers may be predictive of MACE in patients with ACS, although higher-quality studies are needed to confirm these observations.
Collapse
Affiliation(s)
- Jaquelina Y T Yiu
- Wellington Cardiovascular Research Group, Department of Surgery & Anaesthesia, University of Otago, PO Box 7343, Wellington, New Zealand
| | - Kathryn E Hally
- Wellington Cardiovascular Research Group, Department of Surgery & Anaesthesia, University of Otago, PO Box 7343, Wellington, New Zealand
| | - Peter D Larsen
- Wellington Cardiovascular Research Group, Department of Surgery & Anaesthesia, University of Otago, PO Box 7343, Wellington, New Zealand
| | - Ana S Holley
- Wellington Cardiovascular Research Group, Department of Surgery & Anaesthesia, University of Otago, PO Box 7343, Wellington, New Zealand.
| |
Collapse
|
32
|
Oluwafunmilayo Ajayi J, Bukoye Oyewo E, Sanmi Adekunle A, Temidayo Ige P, Ayomide Akomolafe P. Subchronic doses of artemether-lumefantrine, ciprofloxacin and diclofenac precipitated inflammatory and immunological dysfunctions in female Wistar rats. Cytokine 2024; 176:156515. [PMID: 38290256 DOI: 10.1016/j.cyto.2024.156515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 01/15/2024] [Accepted: 01/18/2024] [Indexed: 02/01/2024]
Abstract
Recents reports have shown increases in the abuse of anti-malaria, antibiotic and analgesic drugs. This study evaluated the effects of co-administration of artemether-lumefantrine (AL), ciprofloxacin (CPX) and diclofenac (DFC) on inflammatory and immunological status of female Wistar rats. Ninety-six female Wistar rats were assigned into eight groups of twelve animals each. Group A was control, groups B, C, D, E, F, G and H were administered AL, CPX, DFC, AL + CPX, AL + DFC, CPX + DFC and AL + CPX + DFC respectively. Dosages of administered drugs were 178 mg/kg b/w of AL, 185 mg/kg b/w of CPX and 9 mg/kg b/w of DFC. Animals were sacrificed after 6 and 12 weeks of oral administration. Blood was obtained through cardiac puncture. The liver was harvested and processed for immunohistochemical analysis. Differential leukocyte count and neutrophil adhesion test was conducted on whole blood. Immunological response was assessed by the serum levels of C-reactive protein (CRP), interleukin-1β (Il-1β), interleukin-6 (Il-6), monocyte chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1), myeloperoxidase, and total immunoglobulin G. Data were analyzed with Graph pad prism 5, using one way analysis of variance at 5 % level of significance. Total leukocyte, lymphocyte and basophils count increased (p<0.05) in B, C, E, F, G and H, while neutrophil count decreased (p<0.05) in D, E, G and H at 6 weeks. Neutrophil adhesion decreased (p<0.05) in B, E, F, G and H at 6 weeks. There was no significant difference (p>0.05) in the expression of Il-6, MCP-1 and VCAM-1 across the groups. Il-1β decreased in H, while CRP increased in H at 6 weeks and 12 weeks. MPO activity decreased (p<0.05) in B, C, D, E, G and H at 6 weeks, but increased (p<0.05) in D and G at 12 weeks. Immunohistochemical analysis indicated increase (p<0.05) in tumour necrosis factor-α in liver tissues of B, C, D, E, F and G, while nuclear factor erythroid 2-related factor 2 increased (p<0.05) in C, D, E, F and G, but decreased (p<0.05) in H at 12 weeks. The co-administration of AL, CPX and DFC induced inflammatory responses with attendant immunological dysfunctions and liver damage.
Collapse
Affiliation(s)
- Juliana Oluwafunmilayo Ajayi
- Department of Biochemistry, Faculty of Basic Medical Sciences, Ladoke Akintola University of Technology, Ogbomoso, Oyo state, Nigeria.
| | - Emmanuel Bukoye Oyewo
- Department of Biochemistry, Faculty of Basic Medical Sciences, Ladoke Akintola University of Technology, Ogbomoso, Oyo state, Nigeria.
| | - Adeniran Sanmi Adekunle
- Department of Biochemistry, Faculty of Basic Medical Sciences, Ladoke Akintola University of Technology, Ogbomoso, Oyo state, Nigeria.
| | - Peace Temidayo Ige
- Bloomberg School of Public Health, John Hopkin University, Baltimore, MD, United States
| | | |
Collapse
|
33
|
Zaiema SEGE, Elwafa MAZMAA, Hassan SGA, El Adwey RHAEF, Ghorab RMM, Galal RESAM. Insight into antiphospholipid syndrome: the role and clinical utility of neutrophils extracellular traps formation. Thromb J 2024; 22:32. [DOI: https:/doi.org/10.1186/s12959-024-00598-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Accepted: 03/14/2024] [Indexed: 04/02/2024] Open
Abstract
AbstractAntiphospholipid syndrome (APLS) is a systemic immune dysregulation distinguished by repetitive complications and pregnancy loss in the absence of definite etiology. Most research focuses on the laboratory detection and clinical features of APLS, but its precise etiology remains to be deeply explored. NETosis is a newly developed theory in the pathophysiology of APLS which may serve as the missing bridge between coagulation and inflammation reaching the disease progression and severity. We aimed in this study to navigate the prognostic role of NETosis in thrombotic APLS. Our study included 49 newly diagnosed APLS patients (both 1ry and 2ry) who met clinical and laboratory criteria as per the international consensus statement on the update of the classification criteria for definite APLS and were sub-classified according to the occurrence of thrombotic events in thrombotic and non-thrombotic types. In addition, 20 sex and age-matched reactive subjects and 20 sex and age-matched healthy volunteer controls were enrolled. NETosis formation was assessed by measuring serum Myeloperoxidase (MPO) and Histones level using the enzyme-linked immunosorbent assay (ELISA) technique. Both MPO and Histones levels were able to discriminate among APLS cases from normal controls, showing significant cutoffs of > 2.09 ng/ml for MPO and > 1.45 ng/ml for Histones (AUC values were 0.987and 1.000, respectively). These values can be used as predictors for NETosis pathophysiology in APLS patients. Additionally, these markers demonstrated a significant association with several prognostic indicators, including thrombosis, higher PT and INR, and lower hemoglobin (Hb) levels which are supposed to be ameliorated by using NETs inhibitors. In conclusion, we suggest that measuring NETosis markers, MPO, and Histones, in the early course of APLS using proposed cutoff values will facilitate the timely initiation of anti-NETosis therapy and improve the overall prognosis, particularly for patients with thrombotic APLS.
Collapse
|
34
|
Zaiema SEGE, Elwafa MAZMAA, Hassan SGA, El Adwey RHAEF, Ghorab RMM, Galal RESAM. Insight into antiphospholipid syndrome: the role and clinical utility of neutrophils extracellular traps formation. Thromb J 2024; 22:32. [PMID: 38549083 PMCID: PMC10979549 DOI: 10.1186/s12959-024-00598-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Accepted: 03/14/2024] [Indexed: 04/01/2024] Open
Abstract
Antiphospholipid syndrome (APLS) is a systemic immune dysregulation distinguished by repetitive complications and pregnancy loss in the absence of definite etiology. Most research focuses on the laboratory detection and clinical features of APLS, but its precise etiology remains to be deeply explored. NETosis is a newly developed theory in the pathophysiology of APLS which may serve as the missing bridge between coagulation and inflammation reaching the disease progression and severity. We aimed in this study to navigate the prognostic role of NETosis in thrombotic APLS. Our study included 49 newly diagnosed APLS patients (both 1ry and 2ry) who met clinical and laboratory criteria as per the international consensus statement on the update of the classification criteria for definite APLS and were sub-classified according to the occurrence of thrombotic events in thrombotic and non-thrombotic types. In addition, 20 sex and age-matched reactive subjects and 20 sex and age-matched healthy volunteer controls were enrolled. NETosis formation was assessed by measuring serum Myeloperoxidase (MPO) and Histones level using the enzyme-linked immunosorbent assay (ELISA) technique. Both MPO and Histones levels were able to discriminate among APLS cases from normal controls, showing significant cutoffs of > 2.09 ng/ml for MPO and > 1.45 ng/ml for Histones (AUC values were 0.987and 1.000, respectively). These values can be used as predictors for NETosis pathophysiology in APLS patients. Additionally, these markers demonstrated a significant association with several prognostic indicators, including thrombosis, higher PT and INR, and lower hemoglobin (Hb) levels which are supposed to be ameliorated by using NETs inhibitors. In conclusion, we suggest that measuring NETosis markers, MPO, and Histones, in the early course of APLS using proposed cutoff values will facilitate the timely initiation of anti-NETosis therapy and improve the overall prognosis, particularly for patients with thrombotic APLS.
Collapse
|
35
|
Sheng M, Cui X. A machine learning-based diagnostic model for myocardial infarction patients: Analysis of neutrophil extracellular traps-related genes and eQTL Mendelian randomization. Medicine (Baltimore) 2024; 103:e37363. [PMID: 38518057 PMCID: PMC10956947 DOI: 10.1097/md.0000000000037363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 02/02/2024] [Indexed: 03/24/2024] Open
Abstract
To identify neutrophil extracellular trap (NET)-associated gene features in the blood of patients with myocardial infarction (MI) using bioinformatics and machine learning, with the aim of exploring potential diagnostic utility in atherosclerosis. The datasets GSE66360 and GSE48060 were downloaded from the Gene Expression Omnibus (GEO) public database. GSE66360 was used as the training set, and GSE48060 was used as an independent validation set. Differential genes related to NETs were screened using R software. Machine learning was performed based on the differential expression of NET-related genes across different samples. The advantages and disadvantages of 4 machine learning algorithms (Random Forest [RF], Extreme Gradient Boosting [XGBoost, XGB], Generalized Linear Models [GLM], and Support Vector Machine-Recursive Feature Elimination [SVM-RFE]) were compared, and the optimal method was used to screen feature genes and construct diagnostic models, which were then validated in the external validation dataset. Correlations between feature genes and immune cells were analyzed, and samples were reclustered based on the expression of feature genes. Differences in downstream molecular mechanisms and immune responses were explored for different clusters. Weighted Gene Co-expression Network Analysis was performed on different clusters, and disease-related NET genes were extracted, followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis. Finally, Mendelian randomization was employed to further investigate the causal relationship between the expression of model genes and the occurrence of MI. Forty-seven NET-related differential genes were obtained, and after comparing the 4 machine learning methods, support vector machine was used to screen ATG7, MMP9, interleukin 6 (IL6), DNASE1, and PDE4B as key genes for the construction of diagnostic models. The diagnostic value of the model was validated in an independent external validation dataset. These five genes showed strong correlations with neutrophils. Different sample clusters also demonstrated differential enrichment in pathways such as nitrogen metabolism, complement and coagulation cascades, cytokine-cytokine receptor interaction, renin-angiotensin system, and steroid biosynthesis. The Mendelian randomization results demonstrate a causal relationship between the expression of ATG7 and the incidence of myocardial infarction. The feature genes ATG7, MMP9, IL6, DNASE1, and PDE4B, identified using bioinformatics, may serve as potential diagnostic biomarkers and therapeutic targets for Myocardial infarction. Specifically, the expression of ATG7 could potentially be a significant factor in the occurrence of MI.
Collapse
Affiliation(s)
- Meng Sheng
- Changde Vocational Technology College, Changde, Hunan, China
| | - Xueying Cui
- Qingyun County People’s Hospital, Qingyun, Shandong, China
| |
Collapse
|
36
|
Zhao S, Li H, Yang F, Yang Y, Zeng Y, An Z, Li J, Wu H, Song J, Wu W. Association of short-term PM 2.5 exposure with airway innate immune response, microbiota and metabolism alterations in human airways. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2024; 345:123435. [PMID: 38295929 DOI: 10.1016/j.envpol.2024.123435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 01/19/2024] [Accepted: 01/21/2024] [Indexed: 02/04/2024]
Abstract
Exposure to fine particulate matter (PM2.5) has been associated with impaired airway innate immunity, leading to diverse lung disorders. However, the mechanisms of the adverse effects of PM2.5 on the airway innate immune system has not been adequately elucidated. This study aimed to investigate the association between short-term exposure to ambient PM2.5 and airway innate immune responses. A panel study of 53 undergraduate students was conducted in November 2020 and April 2021. Levels of airway innate immune biomarkers including interleukin-1β (IL-1β), IL-4, IL-6, IL-8, IL-17, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), myeloperoxidase (MPO), and matrix metalloproteinase-9 (MMP-9) in induced sputum were measured, and airway microbiota and metabolites examined. Linear mixed-effect model was used to evaluate the effects of short-term exposure to PM2.5 on the above-listed airway immune biomarkers. The results indicated that for every 10 μg/m3 increase in PM2.5 concentration (at lag3), was associated with an increase of 21.3 % (5.4 %-37.1 %), 26.2 % (0.30 %-52.1 %), 22.4 % (0.70 %-44.2 %), 27.4 % (6.6 %-48.3 %), 18.3 % (4.6 %-31.9 %), 3.9 % (0.20 %-7.6 %) or 2.4 % (0.10 %-4.7 %) in IL-6, TNF-α, IL-17, IL-4, IFN-γ, MPO, or MMP-9 levels, respectively. Meanwhile, exposure to higher levels of ambient PM2.5 was found to significantly modulate airway microbiota and metabolite profile. Specifically, Prevotella and Fusobacterium, as well as 96 different metabolites were associated with PM2.5 levels. The metabolic pathways associated with these metabolites mainly included amino acid biosynthesis and metabolism. Notably, PM2.5 exposure-induced alterations of some airway microbiota were significantly correlated with specific airway metabolic change. Taken together, these results demonstrated that short-term exposure to PM2.5 was associated with alterations of airway immune response, microbial dysbiosis and changes of metabolites. This study provided insights into the mechanisms underlying PM2.5-induced airway innate immune responses.
Collapse
Affiliation(s)
- Shuaiqi Zhao
- Henan International Collaborative Laboratory for Health Effects and Intervention of Air Pollution, School of Public Health, Xinxiang Medical University, Xinxiang, Henan Province, 453003, China
| | - Huijun Li
- Henan International Collaborative Laboratory for Health Effects and Intervention of Air Pollution, School of Public Health, Xinxiang Medical University, Xinxiang, Henan Province, 453003, China
| | - Fuyun Yang
- Henan International Collaborative Laboratory for Health Effects and Intervention of Air Pollution, School of Public Health, Xinxiang Medical University, Xinxiang, Henan Province, 453003, China
| | - Yishu Yang
- Henan International Collaborative Laboratory for Health Effects and Intervention of Air Pollution, School of Public Health, Xinxiang Medical University, Xinxiang, Henan Province, 453003, China
| | - Yuling Zeng
- Henan International Collaborative Laboratory for Health Effects and Intervention of Air Pollution, School of Public Health, Xinxiang Medical University, Xinxiang, Henan Province, 453003, China
| | - Zhen An
- Henan International Collaborative Laboratory for Health Effects and Intervention of Air Pollution, School of Public Health, Xinxiang Medical University, Xinxiang, Henan Province, 453003, China
| | - Juan Li
- Henan International Collaborative Laboratory for Health Effects and Intervention of Air Pollution, School of Public Health, Xinxiang Medical University, Xinxiang, Henan Province, 453003, China
| | - Hui Wu
- Henan International Collaborative Laboratory for Health Effects and Intervention of Air Pollution, School of Public Health, Xinxiang Medical University, Xinxiang, Henan Province, 453003, China
| | - Jie Song
- Henan International Collaborative Laboratory for Health Effects and Intervention of Air Pollution, School of Public Health, Xinxiang Medical University, Xinxiang, Henan Province, 453003, China
| | - Weidong Wu
- Henan International Collaborative Laboratory for Health Effects and Intervention of Air Pollution, School of Public Health, Xinxiang Medical University, Xinxiang, Henan Province, 453003, China.
| |
Collapse
|
37
|
Yano J, Fidel PL. Impaired neutrophil extracellular trap-forming capacity contributes to susceptibility to chronic vaginitis in a mouse model of vulvovaginal candidiasis. Infect Immun 2024; 92:e0035023. [PMID: 38289125 DOI: 10.1128/iai.00350-23] [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: 08/31/2023] [Accepted: 01/04/2024] [Indexed: 03/13/2024] Open
Abstract
Vulvovaginal candidiasis (VVC), caused by Candida albicans, is characterized by aberrant inflammation by polymorphonuclear neutrophils (PMNs) in the vaginal lumen. Data from the established murine model shows that despite potent antifungal properties, PMNs fail to clear C. albicans due to local heparan sulfate that inhibits the interaction between PMNs and C. albicans, resulting in chronic vaginal immunopathology. To understand the role of neutrophil extracellular traps (NETs) in defense against C. albicans at the vaginal mucosa, we investigated the NET-forming capacity of PMNs in chronic VVC-susceptible (CVVC-S/C3H) and -resistant (CVVC-R/CD-1) mouse strains. Immunofluorescence revealed the formation of NETs (release of DNA with PMN-derived antimicrobial proteins) in PMN-C. albicans cocultures using vaginal conditioned medium (VCM) generated from CVVC-R/CD-1 mice, similar to NET-inducing positive controls. Under these NETotic conditions, PMNs released high levels of double-stranded DNA bound with NET-associated proteins, concomitant with substantial C. albicans killing activity. In contrast, PMN-C. albicans cocultures in VCM from CVVC-S/C3H mice lacked NET formation together with reduced antifungal activity. Similar results were observed in vivo: active NET-C. albicans interaction followed by fungal clearance in inoculated CVVC-R/CD-1 mice, and sustained high vaginal fungal burden and no evidence of NETs in inoculated CVVC-S/C3H mice. Furthermore, the level of Ki67 expression, a putative NETotic PMN marker, was significantly reduced in vaginal lavage fluid from CVVC-S/C3H mice compared to CVVC-R/CD-1 mice. Finally, scanning electron microscopy revealed that PMNs in CVVC-R, but not CVVC-S, conditions exhibited NETs in direct contact with C. albicans hyphae in vitro and in vivo. These results suggest that VVC-associated immunopathology includes impaired NET-mediated antifungal activity.
Collapse
Affiliation(s)
- Junko Yano
- Department of Oral and Craniofacial Biology, Louisiana State University Health, New Orleans, Louisiana, USA
| | | |
Collapse
|
38
|
García-Culebras A, Cuartero MI, Peña-Martínez C, Moraga A, Vázquez-Reyes S, de Castro-Millán FJ, Cortes-Canteli M, Lizasoain I, Moro MÁ. Myeloid cells in vascular dementia and Alzheimer's disease: Possible therapeutic targets? Br J Pharmacol 2024; 181:777-798. [PMID: 37282844 DOI: 10.1111/bph.16159] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Revised: 05/10/2023] [Accepted: 05/20/2023] [Indexed: 06/08/2023] Open
Abstract
Growing evidence supports the suggestion that the peripheral immune system plays a role in different pathologies associated with cognitive impairment, such as vascular dementia (VD) or Alzheimer's disease (AD). The aim of this review is to summarize, within the peripheral immune system, the implications of different types of myeloid cells in AD and VD, with a special focus on post-stroke cognitive impairment and dementia (PSCID). We will review the contributions of the myeloid lineage, from peripheral cells (neutrophils, platelets, monocytes and monocyte-derived macrophages) to central nervous system (CNS)-associated cells (perivascular macrophages and microglia). Finally, we will evaluate different potential strategies for pharmacological modulation of pathological processes mediated by myeloid cell subsets, with an emphasis on neutrophils, their interaction with platelets and the process of immunothrombosis that triggers neutrophil-dependent capillary stall and hypoperfusion, as possible effector mechanisms that may pave the way to novel therapeutic avenues to stop dementia, the epidemic of our time. LINKED ARTICLES: This article is part of a themed issue From Alzheimer's Disease to Vascular Dementia: Different Roads Leading to Cognitive Decline. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.6/issuetoc.
Collapse
Affiliation(s)
- Alicia García-Culebras
- Cardiovascular Risk Factor and Brain Function Programme, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
- Unidad de Investigación Neurovascular, Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Madrid, Spain
- Departamento de Biología Celular, Facultad de Medicina, UCM, Madrid, Spain
- Instituto Universitario de Investigación en Neuroquímica, UCM, Madrid, Spain
| | - María Isabel Cuartero
- Cardiovascular Risk Factor and Brain Function Programme, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
- Unidad de Investigación Neurovascular, Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Madrid, Spain
- Instituto Universitario de Investigación en Neuroquímica, UCM, Madrid, Spain
| | - Carolina Peña-Martínez
- Cardiovascular Risk Factor and Brain Function Programme, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
- Unidad de Investigación Neurovascular, Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Madrid, Spain
- Instituto Universitario de Investigación en Neuroquímica, UCM, Madrid, Spain
| | - Ana Moraga
- Unidad de Investigación Neurovascular, Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Madrid, Spain
- Departamento de Biología Celular, Facultad de Medicina, UCM, Madrid, Spain
- Instituto Universitario de Investigación en Neuroquímica, UCM, Madrid, Spain
- Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain
| | - Sandra Vázquez-Reyes
- Cardiovascular Risk Factor and Brain Function Programme, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
- Unidad de Investigación Neurovascular, Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Madrid, Spain
- Instituto Universitario de Investigación en Neuroquímica, UCM, Madrid, Spain
| | - Francisco Javier de Castro-Millán
- Cardiovascular Risk Factor and Brain Function Programme, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
- Unidad de Investigación Neurovascular, Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Madrid, Spain
- Instituto Universitario de Investigación en Neuroquímica, UCM, Madrid, Spain
| | - Marta Cortes-Canteli
- Cardiovascular Risk Factor and Brain Function Programme, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
- Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain
| | - Ignacio Lizasoain
- Unidad de Investigación Neurovascular, Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Madrid, Spain
- Instituto Universitario de Investigación en Neuroquímica, UCM, Madrid, Spain
- Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain
| | - María Ángeles Moro
- Cardiovascular Risk Factor and Brain Function Programme, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
- Unidad de Investigación Neurovascular, Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Madrid, Spain
- Instituto Universitario de Investigación en Neuroquímica, UCM, Madrid, Spain
- Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain
| |
Collapse
|
39
|
Bowman J, Lynch VJ. Rapid evolution of genes with anti-cancer functions during the origins of large bodies and cancer resistance in elephants. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.27.582135. [PMID: 38463968 PMCID: PMC10925141 DOI: 10.1101/2024.02.27.582135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/12/2024]
Abstract
Elephants have emerged as a model system to study the evolution of body size and cancer resistance because, despite their immense size, they have a very low prevalence of cancer. Previous studies have found that duplication of tumor suppressors at least partly contributes to the evolution of anti-cancer cellular phenotypes in elephants. Still, many other mechanisms must have contributed to their augmented cancer resistance. Here, we use a suite of codon-based maximum-likelihood methods and a dataset of 13,310 protein-coding gene alignments from 261 Eutherian mammals to identify positively selected and rapidly evolving elephant genes. We found 496 genes (3.73% of alignments tested) with statistically significant evidence for positive selection and 660 genes (4.96% of alignments tested) that likely evolved rapidly in elephants. Positively selected and rapidly evolving genes are statistically enriched in gene ontology terms and biological pathways related to regulated cell death mechanisms, DNA damage repair, cell cycle regulation, epidermal growth factor receptor (EGFR) signaling, and immune functions, particularly neutrophil granules and degranulation. All of these biological factors are plausibly related to the evolution of cancer resistance. Thus, these positively selected and rapidly evolving genes are promising candidates for genes contributing to elephant-specific traits, including the evolution of molecular and cellular characteristics that enhance cancer resistance.
Collapse
Affiliation(s)
- Jacob Bowman
- Department of Biological Sciences, University at Buffalo, SUNY, 551 Cooke Hall, Buffalo, NY, 14260, USA
| | - Vincent J. Lynch
- Department of Biological Sciences, University at Buffalo, SUNY, 551 Cooke Hall, Buffalo, NY, 14260, USA
| |
Collapse
|
40
|
Osorio M, Velásquez I, Vargas R, Vanegas-García A, Rojas M, Vásquez G, Muñoz-Vahos C. NETosis Secondary to the Use of Levamisole-Adulterated Cocaine: A Likely Underlying Mechanism of Vasculopathy. J Toxicol 2024; 2024:7388799. [PMID: 38434602 PMCID: PMC10904679 DOI: 10.1155/2024/7388799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 01/31/2024] [Accepted: 02/09/2024] [Indexed: 03/05/2024] Open
Abstract
Background Since 2010, several cases of a new vasculopathy induced by the use of levamisole-adulterated cocaine (LAC) have been reported. This vasculopathy is characterized by retiform purpura, earlobe necrosis, multisystem compromise, and multiple autoantibodies. Given its similarity to antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, LAC-associated vasculopathy is postulated to be mediated by pathophysiologic processes resulting from neutrophil cell death by NETosis, a phenomenon previously described in ANCA vasculitis. This study tries to establish the presence of NETosis induced by cocaine, levamisole, or both. Methodology. Neutrophils were isolated from the peripheral blood of healthy controls by Ficoll-Hystopaque density gradient centrifugation followed by dextran sedimentation. Cell viability and purity were evaluated by flow cytometry after staining with PI/DiOC6 and labeling with fluorescent anti-CD45/anti-CD3 monoclonal antibodies (mAbs), respectively. Neutrophils were exposed to levamisole, cocaine, a cocaine-levamisole mixture, and sera pools from healthy controls and patients with LAC-associated vasculopathy. NETosis was then assessed by flow cytometry after staining cells with Sytox Green, Hoechst-33342, and fluorescent antineutrophil elastase (NE) and antimyeloperoxidase (MPO) mAbs. In addition, NETosis was morphologically confirmed by fluorescence microscopy. Proinflammatory cytokine levels in culture supernatants and reactive oxygen species (ROS) synthesis were determined by flow cytometry. The involvement of calcium and muscarinic receptors in cell death induction was evaluated in parallel experiments carried out in the presence of 1,2-bis (o-aminophenoxy) ethane-N, N, N', N'-tetraacetic acid (BAPTA) and hyoscine butylbromide (HBB), their respective inhibitors. Results Cocaine, levamisole, and a cocaine-levamisole mixture induced neutrophil cell death. DNA/MPO extrusion and cell morphology patterns were consistent with NETosis. Neither proinflammatory cytokines nor ROS behaved as proNETotic factors. Preliminary results suggested that muscarinic receptors and calcium-dependent signals were involved in LAC-induced NETosis. Conclusions Cocaine, levamisole, and a cocaine-levamisole mixture can induce NETosis through mechanisms involving muscarinic receptors and calcium-dependent pathways.
Collapse
Affiliation(s)
- Manuela Osorio
- Grupo de Inmunología Celular e Inmunogenética, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia
| | - Isabel Velásquez
- Grupo de Inmunología Celular e Inmunogenética, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia
| | - Ruben Vargas
- Grupo de Inmunología Celular e Inmunogenética, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia
| | - Adriana Vanegas-García
- Hospital Universitario San Vicente Fundación, Medellín, Colombia
- Sección de Reumatología, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia
| | - Mauricio Rojas
- Grupo de Inmunología Celular e Inmunogenética, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia
| | - Gloria Vásquez
- Grupo de Inmunología Celular e Inmunogenética, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia
| | - Carlos Muñoz-Vahos
- Hospital Universitario San Vicente Fundación, Medellín, Colombia
- Sección de Reumatología, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia
| |
Collapse
|
41
|
Zheng R, Moynahan K, Georgomanolis T, Pavlenko E, Geissen S, Mizi A, Grimm S, Nemade H, Rehimi R, Bastigkeit J, Lackmann JW, Adam M, Rada-Iglesias A, Nuernberg P, Klinke A, Poepsel S, Baldus S, Papantonis A, Kargapolova Y. Remodeling of the endothelial cell transcriptional program via paracrine and DNA-binding activities of MPO. iScience 2024; 27:108898. [PMID: 38322992 PMCID: PMC10844825 DOI: 10.1016/j.isci.2024.108898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 12/01/2023] [Accepted: 01/09/2024] [Indexed: 02/08/2024] Open
Abstract
Myeloperoxidase (MPO) is an enzyme that functions in host defense. MPO is released into the vascular lumen by neutrophils during inflammation and may adhere and subsequently penetrate endothelial cells (ECs) coating vascular walls. We show that MPO enters the nucleus of ECs and binds chromatin independently of its enzymatic activity. MPO drives chromatin decondensation at its binding sites and enhances condensation at neighboring regions. It binds loci relevant for endothelial-to-mesenchymal transition (EndMT) and affects the migratory potential of ECs. Finally, MPO interacts with the RNA-binding factor ILF3 thereby affecting its relative abundance between cytoplasm and nucleus. This interaction leads to change in stability of ILF3-bound transcripts. MPO-knockout mice exhibit reduced number of ECs at scar sites following myocardial infarction, indicating reduced neovascularization. In summary, we describe a non-enzymatic role for MPO in coordinating EndMT and controlling the fate of endothelial cells through direct chromatin binding and association with co-factors.
Collapse
Affiliation(s)
- Ruiyuan Zheng
- Department III of Internal Medicine, Heart Center, Faculty of Medicine and University Hospital of Cologne, 50937 Cologne, Germany
| | - Kyle Moynahan
- Department III of Internal Medicine, Heart Center, Faculty of Medicine and University Hospital of Cologne, 50937 Cologne, Germany
| | - Theodoros Georgomanolis
- Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
| | - Egor Pavlenko
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
| | - Simon Geissen
- Department III of Internal Medicine, Heart Center, Faculty of Medicine and University Hospital of Cologne, 50937 Cologne, Germany
| | - Athanasia Mizi
- Institute of Pathology, University Medical Center Göttingen, 37075 Göttingen, Germany
| | - Simon Grimm
- Department III of Internal Medicine, Heart Center, Faculty of Medicine and University Hospital of Cologne, 50937 Cologne, Germany
| | - Harshal Nemade
- Department III of Internal Medicine, Heart Center, Faculty of Medicine and University Hospital of Cologne, 50937 Cologne, Germany
| | - Rizwan Rehimi
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
| | - Jil Bastigkeit
- Department III of Internal Medicine, Heart Center, Faculty of Medicine and University Hospital of Cologne, 50937 Cologne, Germany
| | - Jan-Wilm Lackmann
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
- Cluster of Excellence on Cellular Stress Responses in Age-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
| | - Matti Adam
- Department III of Internal Medicine, Heart Center, Faculty of Medicine and University Hospital of Cologne, 50937 Cologne, Germany
| | - Alvaro Rada-Iglesias
- Institute of Biomedicine and Biotechnology of Cantabria (IBBTEC), University of Cantabria, 39011 Santander, Spain
| | - Peter Nuernberg
- Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany
| | - Anna Klinke
- Department III of Internal Medicine, Heart Center, Faculty of Medicine and University Hospital of Cologne, 50937 Cologne, Germany
| | - Simon Poepsel
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
| | - Stephan Baldus
- Department III of Internal Medicine, Heart Center, Faculty of Medicine and University Hospital of Cologne, 50937 Cologne, Germany
| | - Argyris Papantonis
- Institute of Pathology, University Medical Center Göttingen, 37075 Göttingen, Germany
| | - Yulia Kargapolova
- Department III of Internal Medicine, Heart Center, Faculty of Medicine and University Hospital of Cologne, 50937 Cologne, Germany
| |
Collapse
|
42
|
Grüning NM, Ralser M. Monogenic Disorders of ROS Production and the Primary Anti-Oxidative Defense. Biomolecules 2024; 14:206. [PMID: 38397443 PMCID: PMC10887155 DOI: 10.3390/biom14020206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2024] [Revised: 01/25/2024] [Accepted: 02/01/2024] [Indexed: 02/25/2024] Open
Abstract
Oxidative stress, characterized by an imbalance between the production of reactive oxygen species (ROS) and the cellular anti-oxidant defense mechanisms, plays a critical role in the pathogenesis of various human diseases. Redox metabolism, comprising a network of enzymes and genes, serves as a crucial regulator of ROS levels and maintains cellular homeostasis. This review provides an overview of the most important human genes encoding for proteins involved in ROS generation, ROS detoxification, and production of reduced nicotinamide adenine dinucleotide phosphate (NADPH), and the genetic disorders that lead to dysregulation of these vital processes. Insights gained from studies on inherited monogenic metabolic diseases provide valuable basic understanding of redox metabolism and signaling, and they also help to unravel the underlying pathomechanisms that contribute to prevalent chronic disorders like cardiovascular disease, neurodegeneration, and cancer.
Collapse
Affiliation(s)
- Nana-Maria Grüning
- Department of Biochemistry, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany;
| | - Markus Ralser
- Department of Biochemistry, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany;
- The Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK
- Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
| |
Collapse
|
43
|
Cuadra B, Silva V, Huang YL, Diaz Y, Rivas C, Molina C, Simon V, Bono MR, Morales B, Rosemblatt M, Silva S, Acuña R, Ezquer F, Ezquer M. The Immunoregulatory and Regenerative Potential of Activated Human Stem Cell Secretome Mitigates Acute-on-Chronic Liver Failure in a Rat Model. Int J Mol Sci 2024; 25:2073. [PMID: 38396750 PMCID: PMC10889754 DOI: 10.3390/ijms25042073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 01/31/2024] [Accepted: 02/02/2024] [Indexed: 02/25/2024] Open
Abstract
Acute-on-chronic liver failure (ACLF) is a syndrome marked by sudden liver function decline and multiorgan failure, predominantly acute kidney injury (AKY), in patients with chronic liver disease. Unregulated inflammation is a hallmark of ACLF; however, the key drivers of ACLF are not fully understood. This study explores the therapeutic properties of human mesenchymal stem cell (MSC) secretome, particularly focusing on its enhanced anti-inflammatory and pro-regenerative properties after the in vitro preconditioning of the cells. We evaluated the efficacy of the systemic administration of MSC secretome in preventing liver failure and AKI in a rat ACLF model where chronic liver disease was induced using by the administration of porcine serum, followed by D-galN/LPS administration to induce acute failure. After ACLF induction, animals were treated with saline (ACLF group) or MSC-derived secretome (ACLF-secretome group). The study revealed that MSC-secretome administration strongly reduced liver histological damage in the ACLF group, which was correlated with higher hepatocyte proliferation, increased hepatic and systemic anti-inflammatory molecule levels, and reduced neutrophil and macrophage infiltration. Additionally, renal examination revealed that MSC-secretome treatment mitigated tubular injuries, reduced apoptosis, and downregulated injury markers. These improvements were linked to increased survival rates in the ACLF-secretome group, endorsing MSC secretomes as a promising therapy for multiorgan failure in ACLF.
Collapse
Affiliation(s)
- Barbara Cuadra
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo, Av. La Plaza 680, Las Condes, Santiago 7610658, Chile; (B.C.); (V.S.); (Y.-L.H.); (S.S.); (R.A.); (F.E.)
| | - Veronica Silva
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo, Av. La Plaza 680, Las Condes, Santiago 7610658, Chile; (B.C.); (V.S.); (Y.-L.H.); (S.S.); (R.A.); (F.E.)
| | - Ya-Lin Huang
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo, Av. La Plaza 680, Las Condes, Santiago 7610658, Chile; (B.C.); (V.S.); (Y.-L.H.); (S.S.); (R.A.); (F.E.)
| | - Yael Diaz
- Departamento de Biotecnología, Facultad de Ciencias Naturales, Matemáticas y del Medio Ambiente, Universidad Tecnológica Metropolitana, Las Palmeras 3360, Ñuñoa, Santiago 7800003, Chile; (Y.D.); (C.R.); (C.M.)
| | - Claudio Rivas
- Departamento de Biotecnología, Facultad de Ciencias Naturales, Matemáticas y del Medio Ambiente, Universidad Tecnológica Metropolitana, Las Palmeras 3360, Ñuñoa, Santiago 7800003, Chile; (Y.D.); (C.R.); (C.M.)
| | - Cristobal Molina
- Departamento de Biotecnología, Facultad de Ciencias Naturales, Matemáticas y del Medio Ambiente, Universidad Tecnológica Metropolitana, Las Palmeras 3360, Ñuñoa, Santiago 7800003, Chile; (Y.D.); (C.R.); (C.M.)
| | - Valeska Simon
- Departamento de Biología, Facultad de Ciencias, Universidad del Chile, Las Encinas 3370, Ñuñoa, Santiago 7800020, Chile; (V.S.); (M.R.B.)
| | - Maria Rosa Bono
- Departamento de Biología, Facultad de Ciencias, Universidad del Chile, Las Encinas 3370, Ñuñoa, Santiago 7800020, Chile; (V.S.); (M.R.B.)
| | - Bernardo Morales
- Facultad de Ciencias de la Salud, Universidad del Alba, Atrys Chile, Guardia Vieja 339, Providencia, Santiago 7510249, Chile;
| | - Mario Rosemblatt
- Centro de Ciencia & Vida, Av. Del Valle Norte 725, Huechuraba, Santiago 8580702, Chile;
| | - Sebastian Silva
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo, Av. La Plaza 680, Las Condes, Santiago 7610658, Chile; (B.C.); (V.S.); (Y.-L.H.); (S.S.); (R.A.); (F.E.)
| | - Rodrigo Acuña
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo, Av. La Plaza 680, Las Condes, Santiago 7610658, Chile; (B.C.); (V.S.); (Y.-L.H.); (S.S.); (R.A.); (F.E.)
| | - Fernando Ezquer
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo, Av. La Plaza 680, Las Condes, Santiago 7610658, Chile; (B.C.); (V.S.); (Y.-L.H.); (S.S.); (R.A.); (F.E.)
| | - Marcelo Ezquer
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo, Av. La Plaza 680, Las Condes, Santiago 7610658, Chile; (B.C.); (V.S.); (Y.-L.H.); (S.S.); (R.A.); (F.E.)
| |
Collapse
|
44
|
Mercado-Evans V, Chew C, Serchejian C, Saltzman A, Mejia ME, Zulk JJ, Cornax I, Nizet V, Patras KA. Tamm-Horsfall protein augments neutrophil NETosis during urinary tract infection. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.01.578501. [PMID: 38370726 PMCID: PMC10871275 DOI: 10.1101/2024.02.01.578501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/20/2024]
Abstract
Urinary neutrophils are a hallmark of urinary tract infection (UTI), yet the mechanisms governing their activation, function, and efficacy in controlling infection remain incompletely understood. Tamm-Horsfall glycoprotein (THP), the most abundant protein in urine, uses terminal sialic acids to bind an inhibitory receptor and dampen neutrophil inflammatory responses. We hypothesized that neutrophil modulation is an integral part of THP-mediated host protection. In a UTI model, THP-deficient mice showed elevated urinary tract bacterial burdens, increased neutrophil recruitment, and more severe tissue histopathological changes compared to WT mice. Furthermore, THP-deficient mice displayed impaired urinary NETosis during UTI. To investigate the impact of THP on NETosis, we coupled in vitro fluorescence-based NET assays, proteomic analyses, and standard and imaging flow cytometry with peripheral human neutrophils. We found that THP increases proteins involved in respiratory chain, neutrophil granules, and chromatin remodeling pathways, enhances NETosis in an ROS-dependent manner, and drives NET-associated morphologic features including nuclear decondensation. These effects were observed only in the presence of a NETosis stimulus and could not be solely replicated with equivalent levels of sialic acid alone. We conclude that THP is a critical regulator of NETosis in the urinary tract, playing a key role in host defense against UTI.
Collapse
Affiliation(s)
- Vicki Mercado-Evans
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
- Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas, USA
| | - Claude Chew
- Cytometry and Cell Sorting Core, Baylor College of Medicine, Houston, Texas, USA
| | - Camille Serchejian
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
| | - Alexander Saltzman
- Mass Spectrometry Proteomics Core, Baylor College of Medicine, Houston, Texas, USA
| | - Marlyd E. Mejia
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
| | - Jacob J. Zulk
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
| | - Ingrid Cornax
- Department of Pediatrics, UC San Diego, La Jolla, California, USA
| | - Victor Nizet
- Department of Pediatrics, UC San Diego, La Jolla, California, USA
- Skaggs School of Pharmacy and Pharmaceutical Sciences, UC San Diego, La Jolla, California, USA
| | - Kathryn A. Patras
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
- Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, Texas, USA
| |
Collapse
|
45
|
Tu H, Ren H, Jiang J, Shao C, Shi Y, Li P. Dying to Defend: Neutrophil Death Pathways and their Implications in Immunity. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2306457. [PMID: 38044275 PMCID: PMC10885667 DOI: 10.1002/advs.202306457] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 11/06/2023] [Indexed: 12/05/2023]
Abstract
Neutrophils, accounting for ≈70% of human peripheral leukocytes, are key cells countering bacterial and fungal infections. Neutrophil homeostasis involves a balance between cell maturation, migration, aging, and eventual death. Neutrophils undergo different death pathways depending on their interactions with microbes and external environmental cues. Neutrophil death has significant physiological implications and leads to distinct immunological outcomes. This review discusses the multifarious neutrophil death pathways, including apoptosis, NETosis, pyroptosis, necroptosis, and ferroptosis, and outlines their effects on immune responses and disease progression. Understanding the multifaceted aspects of neutrophil death, the intersections among signaling pathways and ramifications of immunity will help facilitate the development of novel therapeutic methods.
Collapse
Affiliation(s)
- Haiyue Tu
- The First Affiliated Hospital of Soochow UniversityState Key Laboratory of Radiation Medicine and ProtectionInstitutes for Translational MedicineSuzhou Medical College of Soochow UniversitySuzhouJiangsu215123China
| | - Haoyu Ren
- The First Affiliated Hospital of Soochow UniversityState Key Laboratory of Radiation Medicine and ProtectionInstitutes for Translational MedicineSuzhou Medical College of Soochow UniversitySuzhouJiangsu215123China
| | - Junjie Jiang
- The First Affiliated Hospital of Soochow UniversityState Key Laboratory of Radiation Medicine and ProtectionInstitutes for Translational MedicineSuzhou Medical College of Soochow UniversitySuzhouJiangsu215123China
| | - Changshun Shao
- The First Affiliated Hospital of Soochow UniversityState Key Laboratory of Radiation Medicine and ProtectionInstitutes for Translational MedicineSuzhou Medical College of Soochow UniversitySuzhouJiangsu215123China
| | - Yufang Shi
- The First Affiliated Hospital of Soochow UniversityState Key Laboratory of Radiation Medicine and ProtectionInstitutes for Translational MedicineSuzhou Medical College of Soochow UniversitySuzhouJiangsu215123China
| | - Peishan Li
- The First Affiliated Hospital of Soochow UniversityState Key Laboratory of Radiation Medicine and ProtectionInstitutes for Translational MedicineSuzhou Medical College of Soochow UniversitySuzhouJiangsu215123China
| |
Collapse
|
46
|
Dumont BL, Neagoe PE, Charles E, Villeneuve L, Tardif JC, Räkel A, White M, Sirois MG. Low-Density Neutrophils Contribute to Subclinical Inflammation in Patients with Type 2 Diabetes. Int J Mol Sci 2024; 25:1674. [PMID: 38338951 PMCID: PMC10855851 DOI: 10.3390/ijms25031674] [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: 01/09/2024] [Revised: 01/24/2024] [Accepted: 01/25/2024] [Indexed: 02/12/2024] Open
Abstract
Type 2 diabetes (T2D) is characterized by low-grade inflammation. Low-density neutrophils (LDNs) represent normally less than 2% of total neutrophils but increase in multiple pathologies, releasing inflammatory cytokines and neutrophil extracellular traps (NETs). We assessed the count and role of high-density neutrophils (HDNs), LDNs, and NET-related activities in patients with T2D. HDNs and LDNs were purified by fluorescence-activated cell sorting (FACS) and counted by flow cytometry. Circulating inflammatory and NETs biomarkers were measured by ELISA (Enzyme Linked Immunosorbent Assay). NET formation was quantified by confocal microscopy. Neutrophil adhesion onto a human extracellular matrix (hECM) was assessed by optical microscopy. We recruited 22 healthy volunteers (HVs) and 18 patients with T2D. LDN counts in patients with diabetes were significantly higher (160%), along with circulating NETs biomarkers (citrullinated H3 histone (H3Cit), myeloperoxidase (MPO), and MPO-DNA (137%, 175%, and 69%, respectively) versus HV. Circulating interleukins (IL-6 and IL-8) and C-Reactive Protein (CRP) were significantly increased by 117%, 171%, and 79%, respectively, in patients compared to HVs. Isolated LDNs from patients expressed more H3Cit, MPO, and NETs, formed more NETs, and adhered more on hECM compared to LDNs from HVs. Patients with T2D present higher levels of circulating LDN- and NET-related biomarkers and associated pro-inflammatory activities.
Collapse
Affiliation(s)
- Benjamin L. Dumont
- Research Center, Montreal Heart Institute, Montreal, QC H1T 1C8, Canada; (B.L.D.); (P.-E.N.); (E.C.); (L.V.); (J.-C.T.)
- Department of Pharmacology and Physiology, Faculty of Medicine, Université de Montréal, Montreal, QC H3C 3J7, Canada
| | - Paul-Eduard Neagoe
- Research Center, Montreal Heart Institute, Montreal, QC H1T 1C8, Canada; (B.L.D.); (P.-E.N.); (E.C.); (L.V.); (J.-C.T.)
| | - Elcha Charles
- Research Center, Montreal Heart Institute, Montreal, QC H1T 1C8, Canada; (B.L.D.); (P.-E.N.); (E.C.); (L.V.); (J.-C.T.)
- Department of Pharmacology and Physiology, Faculty of Medicine, Université de Montréal, Montreal, QC H3C 3J7, Canada
| | - Louis Villeneuve
- Research Center, Montreal Heart Institute, Montreal, QC H1T 1C8, Canada; (B.L.D.); (P.-E.N.); (E.C.); (L.V.); (J.-C.T.)
| | - Jean-Claude Tardif
- Research Center, Montreal Heart Institute, Montreal, QC H1T 1C8, Canada; (B.L.D.); (P.-E.N.); (E.C.); (L.V.); (J.-C.T.)
- Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada;
| | - Agnès Räkel
- Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada;
- Research Center, Centre Hospitalier de l’Université de Montréal (CHUM), Montreal, QC H2X 0A9, Canada
| | - Michel White
- Research Center, Montreal Heart Institute, Montreal, QC H1T 1C8, Canada; (B.L.D.); (P.-E.N.); (E.C.); (L.V.); (J.-C.T.)
- Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada;
| | - Martin G. Sirois
- Research Center, Montreal Heart Institute, Montreal, QC H1T 1C8, Canada; (B.L.D.); (P.-E.N.); (E.C.); (L.V.); (J.-C.T.)
- Department of Pharmacology and Physiology, Faculty of Medicine, Université de Montréal, Montreal, QC H3C 3J7, Canada
| |
Collapse
|
47
|
Zhou X, Jin J, Lv T, Song Y. A Narrative Review: The Role of NETs in Acute Respiratory Distress Syndrome/Acute Lung Injury. Int J Mol Sci 2024; 25:1464. [PMID: 38338744 PMCID: PMC10855305 DOI: 10.3390/ijms25031464] [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: 11/09/2023] [Revised: 12/14/2023] [Accepted: 01/16/2024] [Indexed: 02/12/2024] Open
Abstract
Nowadays, acute respiratory distress syndrome (ARDS) still has a high mortality rate, and the alleviation and treatment of ARDS remains a major research focus. There are various causes of ARDS, among which pneumonia and non-pulmonary sepsis are the most common. Trauma and blood transfusion can also cause ARDS. In ARDS, the aggregation and infiltration of neutrophils in the lungs have a great influence on the development of the disease. Neutrophils regulate inflammatory responses through various pathways, and the release of neutrophils through neutrophil extracellular traps (NETs) is considered to be one of the most important mechanisms. NETs are mainly composed of DNA, histones, and granuloproteins, all of which can mediate downstream signaling pathways that can activate inflammatory responses, generate immune clots, and cause damage to surrounding tissues. At the same time, the components of NETs can also promote the formation and release of NETs, thus forming a vicious cycle that continuously aggravates the progression of the disease. NETs are also associated with cytokine storms and immune balance. Since DNA is the main component of NETs, DNase I is considered a viable drug for removing NETs. Other therapeutic methods to inhibit the formation of NETs are also worthy of further exploration. This review discusses the formation and mechanism of NETs in ARDS. Understanding the association between NETs and ARDS may help to develop new perspectives on the treatment of ARDS.
Collapse
Affiliation(s)
| | | | - Tangfeng Lv
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210093, China; (X.Z.); (J.J.)
| | - Yong Song
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210093, China; (X.Z.); (J.J.)
| |
Collapse
|
48
|
Lin W, Chen H, Chen X, Guo C. The Roles of Neutrophil-Derived Myeloperoxidase (MPO) in Diseases: The New Progress. Antioxidants (Basel) 2024; 13:132. [PMID: 38275657 PMCID: PMC10812636 DOI: 10.3390/antiox13010132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 01/06/2024] [Accepted: 01/12/2024] [Indexed: 01/27/2024] Open
Abstract
Myeloperoxidase (MPO) is a heme-containing peroxidase, mainly expressed in neutrophils and, to a lesser extent, in monocytes. MPO is known to have a broad bactericidal ability via catalyzing the reaction of Cl- with H2O2 to produce a strong oxidant, hypochlorous acid (HOCl). However, the overproduction of MPO-derived oxidants has drawn attention to its detrimental role, especially in diseases characterized by acute or chronic inflammation. Broadly speaking, MPO and its derived oxidants are involved in the pathological processes of diseases mainly through the oxidation of biomolecules, which promotes inflammation and oxidative stress. Meanwhile, some researchers found that MPO deficiency or using MPO inhibitors could attenuate inflammation and tissue injuries. Taken together, MPO might be a promising target for both prognostic and therapeutic interventions. Therefore, understanding the role of MPO in the progress of various diseases is of great value. This review provides a comprehensive analysis of the diverse roles of MPO in the progression of several diseases, including cardiovascular diseases (CVDs), neurodegenerative diseases, cancers, renal diseases, and lung diseases (including COVID-19). This information serves as a valuable reference for subsequent mechanistic research and drug development.
Collapse
Affiliation(s)
- Wei Lin
- Clinical Pharmacology Research Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China;
| | - Huili Chen
- Center of System Pharmacology and Pharmacometrics, College of Pharmacy, University of Florida, Gainesville, FL 32611, USA;
| | - Xijing Chen
- Clinical Pharmacology Research Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China;
| | - Chaorui Guo
- Clinical Pharmacology Research Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China;
| |
Collapse
|
49
|
Rawat S, Kumar S, Duggal S, Banerjee A. Phenotypic alteration by dengue virus serotype 2 delays neutrophil apoptosis and stimulates the release of prosurvival secretome with immunomodulatory functions. J Leukoc Biol 2024; 115:276-292. [PMID: 37890093 DOI: 10.1093/jleuko/qiad133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 09/29/2023] [Accepted: 10/10/2023] [Indexed: 10/29/2023] Open
Abstract
Neutrophils are the most abundant granuloytes, are phenotypically heterogeneous, and exert detrimental or protective roles during antiviral response. Dengue virus has been reported to activate neutrophils. However, the effect of the dengue virus on the neutrophil phenotypes, survival, and release of inflammatory secretome is yet to be understood. Herein, we investigated the effect of dengue virus serotype 2 (DV-2) on effector functions of naïve neutrophils and studied the impact of its secretome on different immune cells. We found that DV-2 activates purified human neutrophils and causes a significant shift toward the CD16bright/CD62Ldim subtype in a multiplicity of infection and time-dependent manner. These phenotypically altered neutrophils show delayed apoptosis through nuclear factor κB and PI3K pathways and have decreased phagocytic capacity. Treatment of neutrophils with myeloperoxidase and PAD4 inhibitor before DV-2 incubation significantly reduced DV-2-induced double-stranded DNA release, suggesting that myeloperoxidase and PAD4 were involved at early stages for the neutrophil activation and double-stranded DNA release. We also report that DV-2-stimulated neutrophil secretome had a significant effect on viral infection, platelet activation, and naïve neutrophil survival via binding of tumor necrosis factor α to tumor necrosis factor receptor 1/2 receptors. Furthermore, incubation of endothelial cells with the DV-2-stimulated neutrophil secretome potentially inhibits proliferation and wound healing capacity and induces endothelial cell death, which can contribute to endothelial barrier dysfunction. In conclusion, the neutrophil-DV-2 interaction modulates the phenotype of neutrophils and the release of prosurvival and antiviral secretome that may act as a double-edged sword during dengue pathogenesis.
Collapse
Affiliation(s)
- Surender Rawat
- Laboratory of Virology, Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurugram Expressway, Faridabad, 121001, Haryana, India
| | - Shubham Kumar
- Laboratory of Virology, Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurugram Expressway, Faridabad, 121001, Haryana, India
| | - Shweta Duggal
- Laboratory of Virology, Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurugram Expressway, Faridabad, 121001, Haryana, India
| | - Arup Banerjee
- Laboratory of Virology, Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurugram Expressway, Faridabad, 121001, Haryana, India
| |
Collapse
|
50
|
He J, Zhang J, Liao X, Xiao Y, Li J, Zheng Z, Chen D, Chen J. Upregulation of PD-1/PD-L1 and downregulation of immune signaling pathways lead to more severe visceral leishmaniasis in undernutrition mice. Parasit Vectors 2024; 17:8. [PMID: 38185681 PMCID: PMC10773036 DOI: 10.1186/s13071-023-06018-2] [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: 05/05/2023] [Accepted: 10/16/2023] [Indexed: 01/09/2024] Open
Abstract
BACKGROUND Leishmaniasis is mainly prevalent in tropical and subtropical developing countries, where chronic undernutrition often co-exists. Undernutrition is reported to promote the progression of leishmaniasis, but its immune mechanisms have not been fully elucidated. METHODS To simulate chronic undernutrition of patients in epidemic areas and explore the immune mechanism of undernutrition promoting leishmaniasis, BALB/c mouse models with different nutritional imbalances were established, including undernutrition 75%, undernutrition 65% and obesity mouse models. After infection with Leishmania donovani in these model mice, we focused on evaluating the progress of leishmaniasis in the spleen and liver, the expression of important immunosuppressive and immunoactivation molecules, and changes of spleen transcriptome. The immune signaling pathways enriched by differentially expressed genes and hub genes were analyzed. RESULTS The results showed that among the mouse infection models, undernutrition 75% + infection group had the highest parasite load in the spleen and liver at the 8th week post-infection, possibly due to the continuous increase of PD-1, PD-L1 and TCR. Spleen RNA-seq results suggested that some immune signaling pathways were downregulated in undernutrition 75% + infection group, including neutrophil extracellular trap formation, IL-17 signaling pathway, natural killer cell-mediated cytotoxicity, etc. Among them, neutrophil extracellular trap formation pathway had the largest number of downregulated genes. This also explained why undernutrition 75% + infection group had the highest parasite load. Through PPI network analysis, hub genes such as Lcn2, Ltf, Mpo, Dnaja1, Hspa1a, Hspa1b and Hsph1 were screened out and might play important roles in the process of undernutrition promoting leishmaniasis. CONCLUSIONS Undernutrition upregulated PD-1 and PD-L1 expression and downregulated immune signaling pathways in mice with visceral leishmaniasis. The signaling pathways and hub genes may serve as drug targets or intervention targets for the treatment of leishmaniasis patients with undernutrition.
Collapse
Affiliation(s)
- Jinlei He
- Department of Pathogenic Biology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China
| | - Jianhui Zhang
- Department of Pathogenic Biology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China
| | - Xuechun Liao
- Department of Pathogenic Biology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China
| | - Yuying Xiao
- Department of Pathogenic Biology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China
| | - Jiao Li
- Department of Pathogenic Biology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China
| | - Zhiwan Zheng
- Department of Pathogenic Biology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China
| | - Dali Chen
- Department of Pathogenic Biology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China.
| | - Jianping Chen
- Department of Pathogenic Biology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China.
| |
Collapse
|