Targeting C5aR1 signaling reduced neutrophil extracellular traps and ameliorates COVID-19 pathology
Targeting C5aR1 signaling reduced neutrophil extracellular traps and ameliorates COVID-19 pathology
Abstract Patients with severe COVID-19 develop acute respiratory distress syndrome (ARDS) that may progress to cytokine storm syndrome, organ dysfunction, and death. Considering that complement component 5a (C5a), through its cellular receptor C5aR1, has potent proinflammatory actions, and plays immunopathological roles in inflammatory diseases, we investigated whether C5a/C5aR1 pathway could be involved in COVID-19 pathophysiology. C5a/C5aR1 signaling increased locally in the lung, especially in neutrophils of critically ill COVID-19 patients compared to patients with influenza infection, as well as in the lung tissue of K18-hACE2 Tg mice (Tg mice) infected with SARS-CoV-2. Genetic and pharmacological inhibition of C5aR1 signaling ameliorated lung immunopathology in Tg-infected mice. Mechanistically, we found that C5aR1 signaling drives neutrophil extracellular trap (NET)s-dependent immunopathology. These data confirm the immunopathological role of C5a/C5aR1 signaling in COVID-19 and indicate that antagonist of C5aR1 could be useful for COVID-19 treatment.
Cunha Fernando Q.、Lambrechts Diether、Cunha Thiago M.、Silva Bruna M.、Veras Flavio P.、Cambier Seppe、Damasceno Samara、Batah Sabrina S.、Castro Icaro M. S.、Cebinelli Guilherme C.M.、Nakaya Helder I.、Zamboni Dario S.、Leiria Luiz O.、Alves-Filho Jos¨| C.、Vanderbeke Lore、Feys Simon、Wauters Els、Cunha Larissa D.、Silva Juliana C.、Jorge Daniel M.、K?hl J?rg、Quadros Andreza U.、Fabro Alexandre T.、Allegretti Marcello、Silva Gabriel V. L.、Beretta Fabio、Rodrigues Tamara、Oliveira Ren¨o D.、Louzada-Junior Paulo、Van Mol Pierre、Arruda Eurico、Schneider Ayda H.、Caetit¨| Diego B.、Salina Ana、Wauters Joost、Proost Paul、Gomes Giovanni F.、Nascimento Daniele C.、Martins Ronaldo、Bibo Naira L.、Paiva Isadora M.、Silva Camilla M.、Brandolini Laura
Center for Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeir?o Preto Medical School, University of S?o Paulo||Graduate Program in Basic and Apply Immunology, Ribeir?o Preto Medical School, University of S?o PauloLaboratory of Translational Genetics, Department of Human GeneticsCenter for Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeir?o Preto Medical School, University of S?o Paulo||Graduate Program in Basic and Apply Immunology, Ribeir?o Preto Medical School, University of S?o PauloCenter for Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeir?o Preto Medical School, University of S?o Paulo||Graduate Program in Basic and Apply Immunology, Ribeir?o Preto Medical School, University of S?o PauloCenter for Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeir?o Preto Medical School, University of S?o PauloLaboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega InstituteCenter for Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeir?o Preto Medical School, University of S?o PauloDepartment of Pathology and Legal Medicine, Ribeir?o Preto Medical School, University of S?o PauloHospital Israelita Albert EinsteinCenter for Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeir?o Preto Medical School, University of S?o Paulo||Graduate Program in Basic and Apply Immunology, Ribeir?o Preto Medical School, University of S?o PauloHospital Israelita Albert EinsteinCenter for Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeir?o Preto Medical School, University of S?o Paulo||Department of Cell and Molecular Biology, Ribeir?o Preto Medical School, University of S?o PauloCenter for Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeir?o Preto Medical School, University of S?o Paulo||Graduate Program in Basic and Apply Immunology, Ribeir?o Preto Medical School, University of S?o PauloCenter for Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeir?o Preto Medical School, University of S?o Paulo||Graduate Program in Basic and Apply Immunology, Ribeir?o Preto Medical School, University of S?o PauloLaboratory for Clinical Infectious and Inflammatory Disorders, Department of Microbiology, Immunology and TransplantationLaboratory for Clinical Infectious and Inflammatory Disorders, Department of Microbiology, Immunology and TransplantationLaboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and MetabolismCenter for Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeir?o Preto Medical School, University of S?o Paulo||Department of Cell and Molecular Biology, Ribeir?o Preto Medical School, University of S?o PauloCenter for Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeir?o Preto Medical School, University of S?o PauloDepartment of Cell and Molecular Biology, Ribeir?o Preto Medical School, University of S?o Paulo||Virology Research Center, Ribeir?o Preto Medical School, University of S?o PauloPain Research Center, Department of Anesthesiology, University of Cincinnati College of Medicine||Institute for Systemic Inflammation Research, University of L¨1beckCenter for Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeir?o Preto Medical School, University of S?o PauloDepartment of Pathology and Legal Medicine, Ribeir?o Preto Medical School, University of S?o PauloR&D Department, Domp¨| Farmaceutici s.p.a.Center for Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeir?o Preto Medical School, University of S?o Paulo||Graduate Program in Basic and Apply Immunology, Ribeir?o Preto Medical School, University of S?o PauloLaboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega InstituteCenter for Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeir?o Preto Medical School, University of S?o Paulo||Graduate Program in Basic and Apply Immunology, Ribeir?o Preto Medical School, University of S?o PauloCenter for Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeir?o Preto Medical School, University of S?o Paulo||Divisions of Clinical Immunology, Emergency, Infectious Diseases and Intensive Care Unit, Ribeir?o Preto Medical School, University of S?o PauloCenter for Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeir?o Preto Medical School, University of S?o Paulo||Divisions of Clinical Immunology, Emergency, Infectious Diseases and Intensive Care Unit, Ribeir?o Preto Medical School, University of S?o PauloLaboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and MetabolismDepartment of Cell and Molecular Biology, Ribeir?o Preto Medical School, University of S?o Paulo||Virology Research Center, Ribeir?o Preto Medical School, University of S?o PauloCenter for Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeir?o Preto Medical School, University of S?o PauloCenter for Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeir?o Preto Medical School, University of S?o Paulo||Graduate Program in Basic and Apply Immunology, Ribeir?o Preto Medical School, University of S?o PauloCenter for Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeir?o Preto Medical School, University of S?o Paulo||Department of Cell and Molecular Biology, Ribeir?o Preto Medical School, University of S?o PauloLaboratory for Clinical Infectious and Inflammatory Disorders, Department of Microbiology, Immunology and Transplantation||Medical Intensive Care Unit, University Hospitals LeuvenLaboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega InstituteCenter for Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeir?o Preto Medical School, University of S?o PauloCenter for Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeir?o Preto Medical School, University of S?o Paulo||Graduate Program in Basic and Apply Immunology, Ribeir?o Preto Medical School, University of S?o PauloDepartment of Cell and Molecular Biology, Ribeir?o Preto Medical School, University of S?o Paulo||Virology Research Center, Ribeir?o Preto Medical School, University of S?o PauloCenter for Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeir?o Preto Medical School, University of S?o PauloCenter for Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeir?o Preto Medical School, University of S?o PauloCenter for Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeir?o Preto Medical School, University of S?o Paulo||Graduate Program in Basic and Apply Immunology, Ribeir?o Preto Medical School, University of S?o PauloR&D Department, Domp¨| Farmaceutici s.p.a.
基础医学临床医学药学
COVID-19C5aR1C5aSARS-CoV-2Myeloid cellsNeutrophilsNETs
Cunha Fernando Q.,Lambrechts Diether,Cunha Thiago M.,Silva Bruna M.,Veras Flavio P.,Cambier Seppe,Damasceno Samara,Batah Sabrina S.,Castro Icaro M. S.,Cebinelli Guilherme C.M.,Nakaya Helder I.,Zamboni Dario S.,Leiria Luiz O.,Alves-Filho Jos¨| C.,Vanderbeke Lore,Feys Simon,Wauters Els,Cunha Larissa D.,Silva Juliana C.,Jorge Daniel M.,K?hl J?rg,Quadros Andreza U.,Fabro Alexandre T.,Allegretti Marcello,Silva Gabriel V. L.,Beretta Fabio,Rodrigues Tamara,Oliveira Ren¨o D.,Louzada-Junior Paulo,Van Mol Pierre,Arruda Eurico,Schneider Ayda H.,Caetit¨| Diego B.,Salina Ana,Wauters Joost,Proost Paul,Gomes Giovanni F.,Nascimento Daniele C.,Martins Ronaldo,Bibo Naira L.,Paiva Isadora M.,Silva Camilla M.,Brandolini Laura.Targeting C5aR1 signaling reduced neutrophil extracellular traps and ameliorates COVID-19 pathology[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/2022.07.03.498624.点此复制
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