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 4

DF2593A, a selective C5aR1 antagonist, ameliorates COVID-19 in mice model.

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DF2593A, a selective C5aR1 antagonist, ameliorates COVID-19 in mice mode...
(A) Tg mice were infected with SARS-CoV-2 (2 x 104 PFU, intranasally) and treated with DF2593A (3 mg/kg, p.o) 1 hour before SARS-CoV-2 infection and once a day up to the day of sample collection (5 dpi). (B) Body weight, clinical score, and oxygen saturation were measured daily after infection (n = 11/group, pooled from 2 independent experiments). (C) Representative H&E staining from the harvested lung of the COVID-19 mouse model treated (n = 4) or not (n = 6) with DF2593A. A mock-infected group was used as control (n = 5). Scale bars: 200 μm (4 ×); 100 μm (10 ×). (D) TUNEL staining (green) for detection of apoptotic cells in situ from lung tissue of mice (n = 5/group). (E) Quantification of the lung septal area fraction. (F) Percentage of TUNEL-positive cells in lung tissue. Scale bar: 50 μm. (G) ELISA assays were performed to detect CCL2, CCL3, CCL4, CXCL1, and IL-6 levels in lung homogenate (n = 6/group). A mock-infected group was used as the control group. Data are shown as the mean ± SEM. P values were determined by 1-way ANOVA followed by Bonferroni’s posthoc test (E–G).