C5aR1 signaling triggers lung immunopathology in COVID-19 through neutrophil extracellular traps
Bruna M. Silva, et al.
Bruna M. Silva, et al.
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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

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Figure 6

C5a/C5aR1 signaling is involved in the pathophysiology of COVID-19 through NET formation.

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C5a/C5aR1 signaling is involved in the pathophysiology of COVID-19 throu...
Tgfl/fl (n = 8) and TgcKO (n = 8) mice were infected with SARS-CoV-2 (2 × 104 PFU, intranasally). (A) Representative confocal images showing the presence of NETs in the lung tissue from Tgfl/fl or Infected TgcKO mice. A mock- infected group was performed as control (n = 5). Staining shows nuclei (DAPI, blue), H3Cit (green), and myeloperoxidase (MPO) (red). (B) At 5 dpi, the levels of NETs were quantified by MPO-DNA PicoGreen assay in the supernatant of the lung homogenate. (C) Tg-infected mice were treated with DF2593A (3mg/kg, p.o, n = 6) or vehicle (n = 5/group). Representative confocal images showing the presence of NETs in the lung tissue of Tg-infected mice treated with DF2593A or vehicle (n = 5/group). A mock-infected group was performed as control (n = 5). (D) At 5 dpi, NETs levels were quantified by MPO-DNA PicoGreen assay in the supernatant of the lung homogenate. Data are shown as the mean ± SeM. P values were determined by 1-way ANOVA followed by Bonferroni’s posthoc test (B and D). Scale bar: 50 μm.