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 1

C5a levels and C5AR1 expression in the BAL fluid and cells from patients with COVID- 19.

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C5a levels and C5AR1 expression in the BAL fluid and cells from patients...
An ELISA assay was performed to measure the concentrations of (A) C5a, (B) factor Bb, and (C) C3a in the BAL fluid from patients with influenza (n = 16) and patients with COVID- 19 (n = 16). (B) Paired concentrations of (D) C5a and (E) factor Bb in the plasma and BAL fluid from patients with COVID-19 were determined by ELISA. (F) A different cohort from a previously published data set was reanalyzed and the t-SNE analysis of total cells (65,166) from BAL fluid of patients with non-COVID-19 pneumonia (n = 13) and COVID-19 (n = 22) is shown. (G) Dot plots display the highlighted distribution of C5AR1 for each indicated cell population. (H) Violin plots showing the expression levels of C5aR1 in each type of cell from patients with COVID-19 or with non-COVID-19 pneumonia. (I) The dot plot depicts the scaled and centered expression of an average cell in each cluster and therefore contains negative and positive values. The average expression reflects the mean expression of C5AR1 in each cluster compared with all other cells. (J) Number of cells per cell population [neutrophils (Neu), monocytes/macrophages (Mo/Mac), and dendritic cells (cDC)] that express C5AR1 in the groups of patients with COVID-19 and non-COVID-19 pneumonia. (K) Average expression of C5AR1 per cell for each cell population [neutrophils (Neu), monocytes/macrophages (Mo/Mac), and dendritic cells (cDC)] in the groups of patients with COVID-19 and non-COVID-19 pneumonia. Data are shown as the mean ± SEM. P values were determined by 2-tailed unpaired (A–D, J, and K) or paired (D and E) Student’s t tests followed by Wilcoxon matched-pairs signed rank tests.