C5aR1 signaling triggers lung immunopathology in COVID-19 through neutrophil extracellular traps

被引：17

作者：

Silva, Bruna M. ^{[1
,2
]}

Gomes, Giovanni F. ^{[1
]}

Veras, Flavio P. ^{[1
]}

Cambier, Seppe ^{[3
]}

Silva, Gabriel V. L. ^{[1
,2
]}

Quadros, Andreza U. ^{[1
]}

Caetite, Diego B. ^{[1
,2
]}

Nascimento, Daniele C. ^{[1
,2
]}

Silva, Camilla M. ^{[1
,2
]}

Silva, Juliana C. ^{[1
]}

Damasceno, Samara ^{[1
]}

Schneider, Ayda H. ^{[1
]}

Beretta, Fabio ^{[3
]}

Batah, Sabrina S. ^{[4
]}

Castro, Icaro M. S. ^{[5
]}

Paiva, Isadora M. ^{[1
]}

Rodrigues, Tamara ^{[1
,2
]}

Salina, Ana ^{[1
,6
]}

Martins, Ronaldo ^{[6
,7
]}

Cebinelli, Guilherme C. M. ^{[1
,2
]}

Bibo, Naira L. ^{[1
]}

Jorge, Daniel M. ^{[6
,7
]}

Nakaya, Helder I. ^{[5
]}

Zamboni, Dario S. ^{[1
,6
]}

Leiria, Luiz O. ^{[1
,2
]}

Fabro, Alexandre T. ^{[4
]}

Alves-Filho, Jose C. ^{[1
,2
]}

Arruda, Eurico ^{[6
,7
]}

Louzada-Junior, Paulo ^{[1
,8
,9
,10
]}

Oliveira, Rene D. ^{[1
,8
,9
,10
]}

Cunha, Larissa D. ^{[1
,6
]}

Van Mol, Pierre ^{[11
]}

Vanderbeke, Lore ^{[12
]}

Feys, Simon ^{[12
]}

Wauters, Els ^{[11
]}

Brandolini, Laura ^{[13
]}

Aramini, Andrea ^{[13
]}

Cunha, Fernando Q. ^{[1
,2
]}

Koehl, Joerg ^{[14
,15
]}

Allegretti, Marcello ^{[13
]}

Lambrechts, Diether ^{[4
,16
]}

Wauters, Joost ^{[12
,17
]}

Proost, Paul ^{[3
]}

Cunha, Thiago M. ^{[1
,2
]}

机构：

[1] Univ Sao Paulo, Ctr Res Inflammatory Dis CRID, Dept Pharmacol, Ribeirao Preto, SP, Brazil

[2] Univ Sao Paulo, Ribeirao Preto Med Sch, Grad Program Basic & Appl Immunol, Ribeirao Preto, SP, Brazil

[3] Katholieke Univ Leuven, Rega Inst, Dept Microbiol Immunol & Transplantat, Lab Mol Immunol, Leuven, Belgium

[4] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pathol & Legal Med, Ribeirao Preto, SP, Brazil

[5] Hosp Israelita Albert Einstein, Sao Paulo, Brazil

[6] Univ Sao Paulo, Dept Cell & Mol Biol, Ribeirao Preto, SP, Brazil

[7] Univ Sao Paulo, Virol Res Ctr, Ribeirao Preto, SP, Brazil

[8] Univ Sao Paulo, Div Clin Immunol, Ribeirao Preto, SP, Brazil

[9] Univ Sao Paulo, Div Emergency, Ribeirao Preto, SP, Brazil

[10] Univ Sao Paulo, Infect Dis & Intens Care Unit, Ribeirao Preto Med Sch, Ribeirao Preto, SP, Brazil

[11] Katholieke Univ Leuven, Dept Chron Dis & Metab, Lab Resp Dis & Thorac Surg BREATHE, Leuven, Belgium

[12] Katholieke Univ Leuven, Dept Microbiol Immunol & Transplantat, Lab Clin Infect & Inflammatory Disorders, Leuven, Belgium

[13] Dompe Farmaceut Spa, R&D Dept, Via Campo Pile, Laquila, Italy

[14] Cincinnati Childrens Hosp Med Ctr, Div Immunobiol, Cincinnati, OH USA

[15] Univ Lubeck, Inst Syst Inflammat Res, Ratzebuger Allee, Lubeck, Germany

[16] Katholieke Univ Leuven, VIB, Dept Human Genet, Lab Translat Genet, Leuven, Belgium

[17] Univ Hosp Leuven, Med Intens Care Unit, Leuven, Belgium

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2023年 / 133卷 / 12期

基金：

巴西圣保罗研究基金会;

关键词：

COMPLEMENT ACTIVATION; INHIBITION; TOCILIZUMAB; INFECTIONS; ROLES; CELLS;

D O I：

10.1172/JCI163105

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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 the C5a/C5aR1 pathway could be involved in COVID-19 pathophysiology. C5a/C5aR1 signaling increased locally in the lung, especially in neutrophils of critically ill patients with COVID-19 compared with 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 traps-dependent (NETs-dependent) immunopathology. These data confirm the immunopathological role of C5a/C5aR1 signaling in COVID-19 and indicate that antagonists of C5aR1 could be useful for COVID-19 treatment.

引用

页数：18

共 21 条

[21] Anti-C5a antibody IFX-1 (vilobelimab) treatment versus best supportive care for patients with severe COVID-19 (PANAMO): an exploratory, open-label, phase 2 randomised controlled trial
Vlaar, Alexander P. J.
de Bruin, Sanne
Busch, Matthias
Timmermans, Sjoerd A. M. E. G.
van Zeggeren, Ingeborg E.
Koning, Rutger
ter Horst, Liora
Bulle, Esther B.
van Baarle, Frank E. H. P.
van de Poll, Marcel C. G.
Kemper, E. Marleen
van der Horst, Iwan C. C.
Schultz, Marcus J.
Horn, Janneke
Paulus, Frederique
Bos, Lieuwe D.
Wiersinga, W. Joost
Witzenrath, Martin
Rueckinger, Simon
Pilz, Korinna
Brouwer, Matthijs C.
Guo, Ren-Feng
Heunks, Leo
van Paassen, Pieter
Riedemann, Niels C.
van de Beek, Diederik
LANCET RHEUMATOLOGY, 2020, 2 (12) : E764 - E773

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