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

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 languageEnglish
Article numbere163105
JournalJournal of Clinical Investigation
Volume133
Issue number12
ISSN0021-9738
DOIs
Publication statusPublished - 15.06.2023

Research Areas and Centers

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

DFG Research Classification Scheme

  • 204-05 Immunology
  • 205-22 Clinical Immunology and Allergology

Coronavirus related work

  • Research on SARS-CoV-2 / COVID-19

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