C5aR1 signaling triggers lung immunopathology in COVID-19 through neutrophil extracellular traps
Bruna M. Silva, et al.
Bruna M. Silva, et al.
View: Text | PDF
Research Article Inflammation

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.

Authors

Bruna M. Silva, Giovanni F. Gomes, Flavio P. Veras, Seppe Cambier, Gabriel V.L. Silva, Andreza U. Quadros, Diego B. Caetité, Daniele C. Nascimento, Camilla M. 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

×

Figure 8

C5a is able to directly promote and enhance SARS-CoV-2-induced NETosis.

Options: View larger image (or click on image) Download as PowerPoint
C5a is able to directly promote and enhance SARS-CoV-2-induced NETosis. ...
(A) Isolated human neutrophils were incubated with PBS, DPI, Cl-amidine, or DF2593A for 1 h and then challenged with rhC5a (3 nM) for 4 h. (B) Cells were stained for nuclei (DAPI, blue), NE (green), and MPO (red). (C) Percentage of NETs quantification in these neutrophils supernatants (n = 3 donors). (D) Neutrophils were isolated from healthy donors and incubated with mock, rhC5a (3 nM), and SARS-CoV-2 (MOI = 1.0) for 4 hours. One group of SARS-CoV-2-infected cells was pretreated with rhC5a (3 nM). (E) Representative images of NETs release. Cells were stained for nuclei (DAPI, blue), NE (green), and MPO (red). Scale bar: 50 μm. (F) Percentage of NETs quantification in these neutrophils supernatants (n = 3 donors). Data are shown as the mean ± SEM. P values were determined by 1-way ANOVA followed by Bonferroni’s posthoc test (C and F).