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

Bruna M. Silva; Giovanni F. Gomes; Flavio P. Veras; Seppe Cambier; Gabriel V.L. Silva; Andreza U. Quadros; Diego B. Caetité; Daniele C. Nascimento; Juliana C. Silva; Juliana C. Silva; Samara Damasceno; Ayda H. Schneider; Fabio Beretta; Sabrina S. Batah; Icaro M.S. Castro; Isadora M. Paiva; Tamara Rodrigues; Ana Salina; Ronaldo Martins; Guilherme C.M. Cebinelli; Naira L. Bibo; Daniel M. Jorge; Helder I. Nakaya; Dario S. Zamboni; Luiz O. Leiria; Alexandre T. Fabro; José C. Alves-Filho; Eurico Arruda; Paulo Louzada-Junior; Renê D. Oliveira; Larissa D. Cunha; Pierre Van Mol; Lore Vanderbeke; Simon Feys; Els Wauters; Laura Brandolini; Andrea Aramini; Fernando Q. Cunha; Jörg Köhl; Marcello Allegretti; Diether Lambrechts; Joost Wauters; Paul Proost; Thiago M. Cunha

doi:10.1172/JCI163105

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

Bruna M. Silva, Giovanni F. Gomes, Flavio P. Veras, Seppe Cambier, Gabriel V.L. Silva, Andreza U. Quadros, Diego B. Caetité, Daniele C. Nascimento, Juliana C. Silva, Juliana C. Silva, Samara Damasceno, Ayda H. Schneider, Fabio Beretta, Sabrina S. Batah, Icaro M.S. Castro, Isadora M. Paiva, Tamara Rodrigues, Ana Salina, Ronaldo Martins, Guilherme C.M. CebinelliNaira L. Bibo, Daniel M. Jorge, Helder I. Nakaya, Dario S. Zamboni, Luiz O. Leiria, Alexandre T. Fabro, José C. Alves-Filho, Eurico Arruda, Paulo Louzada-Junior, Renê D. Oliveira, Larissa D. Cunha, Pierre Van Mol, Lore Vanderbeke, Simon Feys, Els Wauters, Laura Brandolini, Andrea Aramini, Fernando Q. Cunha, Jörg Köhl, Marcello Allegretti, Diether Lambrechts, Joost Wauters, Paul Proost, Thiago M. Cunha^*

^*Corresponding author for this work

Institute of Systemic Inflamation Research

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 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.

Original language	English
Article number	e163105
Journal	Journal of Clinical Investigation
Volume	133
Issue number	12
ISSN	0021-9738
DOIs	https://doi.org/10.1172/JCI163105
Publication status	Published - 15.06.2023

Funding

The authors gratefully acknowledge the technical assistance of Ieda R. Schivo, Ana Katia dos Santos, Jenna M. Turner, Sergio R. Rosa, Diva A. Sousa, Eleni Tamburus, Marcella Daruge Grando, Soraya Jabur, Felipe Souza, and Andreia Nogueira. The research leading to these results received funding from a research grant from Dompé Farmaceutici s.p.a (USP/Dompé Farmaceutici s.p.a agreement), KU Leuven (C1 grant C16/17/010), and the São Paulo Research Foundation (FAPESP) under grant agreements no. 2020/04860-8 (COVID-19 project) and 2013/08216-2 (Center for Research in Inflammatory Disease), and a joint grant between FAPESP and Research Foundation Flanders (FWO Vlaanderen) (grant G0F7519N - 18/10990-1). SC is supported by a PhD fellowship from FWO-Vlaanderen.

Research Areas and Centers

Academic Focus: Center for Infection and Inflammation Research (ZIEL)

DFG Research Classification Scheme

2.21-05 Immunology
2.22-22 Clinical Immunology and Allergology

Coronavirus related work

Research on SARS-CoV-2 / COVID-19

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1172/JCI163105

Cite this

Silva, B. M., Gomes, G. F., Veras, F. P., Cambier, S., Silva, G. V. L., Quadros, A. U., Caetité, D. B., Nascimento, D. C., Silva, J. C., Silva, J. C., Damasceno, S., Schneider, A. H., Beretta, F., Batah, S. S., Castro, I. M. S., Paiva, I. M., Rodrigues, T., Salina, A., Martins, R., ... Cunha, T. M. (2023). C5aR1 signaling triggers lung immunopathology in COVID-19 through neutrophil extracellular traps. Journal of Clinical Investigation, 133(12), Article e163105. https://doi.org/10.1172/JCI163105

@article{f5949f79cc6d4edea394b7cea9c9e9f5,

title = "C5aR1 signaling triggers lung immunopathology in COVID-19 through neutrophil extracellular traps",

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 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.",

author = "Silva, \{Bruna M.\} and Gomes, \{Giovanni F.\} and Veras, \{Flavio P.\} and Seppe Cambier and Silva, \{Gabriel V.L.\} and Quadros, \{Andreza U.\} and Caetit{\'e}, \{Diego B.\} and Nascimento, \{Daniele C.\} and Silva, \{Juliana C.\} and Silva, \{Juliana C.\} and Samara Damasceno and Schneider, \{Ayda H.\} and Fabio Beretta and Batah, \{Sabrina S.\} and Castro, \{Icaro M.S.\} and Paiva, \{Isadora M.\} and Tamara Rodrigues and Ana Salina and Ronaldo Martins and Cebinelli, \{Guilherme C.M.\} and Bibo, \{Naira L.\} and Jorge, \{Daniel M.\} and Nakaya, \{Helder I.\} and Zamboni, \{Dario S.\} and Leiria, \{Luiz O.\} and Fabro, \{Alexandre T.\} and Alves-Filho, \{Jos{\'e} C.\} and Eurico Arruda and Paulo Louzada-Junior and Oliveira, \{Ren{\^e} D.\} and Cunha, \{Larissa D.\} and \{Van Mol\}, Pierre and Lore Vanderbeke and Simon Feys and Els Wauters and Laura Brandolini and Andrea Aramini and Cunha, \{Fernando Q.\} and J{\"o}rg K{\"o}hl and Marcello Allegretti and Diether Lambrechts and Joost Wauters and Paul Proost and Cunha, \{Thiago M.\}",

note = "Publisher Copyright: {\textcopyright} 2023, Silva et al.",

year = "2023",

month = jun,

day = "15",

doi = "10.1172/JCI163105",

language = "English",

volume = "133",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "American Society for Clinical Investigation",

number = "12",

}

Silva, BM, Gomes, GF, Veras, FP, Cambier, S, Silva, GVL, Quadros, AU, Caetité, DB, Nascimento, DC, Silva, JC, Silva, JC, Damasceno, S, Schneider, AH, Beretta, F, Batah, SS, Castro, IMS, Paiva, IM, Rodrigues, T, Salina, A, Martins, R, Cebinelli, GCM, Bibo, NL, Jorge, DM, Nakaya, HI, Zamboni, DS, Leiria, LO, Fabro, AT, Alves-Filho, JC, Arruda, E, Louzada-Junior, P, Oliveira, RD, Cunha, LD, Van Mol, P, Vanderbeke, L, Feys, S, Wauters, E, Brandolini, L, Aramini, A, Cunha, FQ, Köhl, J, Allegretti, M, Lambrechts, D, Wauters, J, Proost, P & Cunha, TM 2023, 'C5aR1 signaling triggers lung immunopathology in COVID-19 through neutrophil extracellular traps', Journal of Clinical Investigation, vol. 133, no. 12, e163105. https://doi.org/10.1172/JCI163105

TY - JOUR

T1 - C5aR1 signaling triggers lung immunopathology in COVID-19 through neutrophil extracellular traps

AU - Silva, Bruna M.

AU - Gomes, Giovanni F.

AU - Veras, Flavio P.

AU - Cambier, Seppe

AU - Silva, Gabriel V.L.

AU - Quadros, Andreza U.

AU - Caetité, Diego B.

AU - Nascimento, Daniele C.

AU - Silva, Juliana C.

AU - Damasceno, Samara

AU - Schneider, Ayda H.

AU - Beretta, Fabio

AU - Batah, Sabrina S.

AU - Castro, Icaro M.S.

AU - Paiva, Isadora M.

AU - Rodrigues, Tamara

AU - Salina, Ana

AU - Martins, Ronaldo

AU - Cebinelli, Guilherme C.M.

AU - Bibo, Naira L.

AU - Jorge, Daniel M.

AU - Nakaya, Helder I.

AU - Zamboni, Dario S.

AU - Leiria, Luiz O.

AU - Fabro, Alexandre T.

AU - Alves-Filho, José C.

AU - Arruda, Eurico

AU - Louzada-Junior, Paulo

AU - Oliveira, Renê D.

AU - Cunha, Larissa D.

AU - Van Mol, Pierre

AU - Vanderbeke, Lore

AU - Feys, Simon

AU - Wauters, Els

AU - Brandolini, Laura

AU - Aramini, Andrea

AU - Cunha, Fernando Q.

AU - Köhl, Jörg

AU - Allegretti, Marcello

AU - Lambrechts, Diether

AU - Wauters, Joost

AU - Proost, Paul

AU - Cunha, Thiago M.

PY - 2023/6/15

Y1 - 2023/6/15

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85163902718

UR - https://www.mendeley.com/catalogue/8d08e581-511b-367c-a539-cec0240b4561/

U2 - 10.1172/JCI163105

DO - 10.1172/JCI163105

M3 - Journal articles

C2 - 37104043

AN - SCOPUS:85163902718

SN - 0021-9738

VL - 133

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 12

M1 - e163105

ER -

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

Abstract

Funding

Research Areas and Centers

DFG Research Classification Scheme

Coronavirus related work

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this