Airway epithelial cells and macrophages trigger IL-6-CD95/CD95L axis and mediate initial immunopathology of COVID-19
Thais F.C. Fraga-Silva,
Ualter G. Cipriano,
Marcilio J. Fumagalli,
Giseli F. Correa,
Carlos A. Fuzo,
Douglas dos-Santos,
Fabiola L.A.C. Mestriner,
Christiane Becari,
Andrea Teixeira-Carvalho,
Jordana Coelho-dos-Reis,
Mayra G. Menegueti,
Luiz T.M. Figueiredo,
Larissa D. Cunha,
Olindo A. Martins-Filho,
Marcelo Dias-Baruffi,
Maria Auxiliadora-Martins,
Rita C. Tostes,
Vania L.D. Bonato
Affiliations
Thais F.C. Fraga-Silva
Department of Biochemistry and Immunology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo 14049-900, Brazil
Ualter G. Cipriano
Basic and Applied Immunology Program, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo 14049-900, Brazil
Marcilio J. Fumagalli
Basic and Applied Immunology Program, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo 14049-900, Brazil
Giseli F. Correa
Basic and Applied Immunology Program, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo 14049-900, Brazil
Carlos A. Fuzo
Department of Clinical Analysis, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of Sao Paulo, Ribeirao Preto, Sao Paulo 14049-900, Brazil
Douglas dos-Santos
Department of Cell Biology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo 14049-900, Brazil
Fabiola L.A.C. Mestriner
Department of Surgery and Anatomy, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo 14049-900, Brazil
Christiane Becari
Department of Surgery and Anatomy, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo 14049-900, Brazil
Andrea Teixeira-Carvalho
René Rachou Institute, Oswaldo Cruz Foundation, FIOCRUZ-Minas, Belo Horizonte, Minas Gerais 30190-009, Brazil
Jordana Coelho-dos-Reis
Department of Microbiology, Biological Science Institute, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
Mayra G. Menegueti
Department of General and Specialized Nursing, Ribeirao Preto Nurse School, University of Sao Paulo, Ribeirao Preto, Sao Paulo 14049-900, Brazil
Luiz T.M. Figueiredo
Basic and Applied Immunology Program, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo 14049-900, Brazil; Virology Research Center, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo 14049-900, Brazil
Larissa D. Cunha
Department of Cell Biology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo 14049-900, Brazil
Olindo A. Martins-Filho
René Rachou Institute, Oswaldo Cruz Foundation, FIOCRUZ-Minas, Belo Horizonte, Minas Gerais 30190-009, Brazil
Marcelo Dias-Baruffi
Department of Clinical Analysis, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of Sao Paulo, Ribeirao Preto, Sao Paulo 14049-900, Brazil
Maria Auxiliadora-Martins
Department of Surgery and Anatomy, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo 14049-900, Brazil
Rita C. Tostes
Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo 14049-900, Brazil
Vania L.D. Bonato
Department of Biochemistry and Immunology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo 14049-900, Brazil; Basic and Applied Immunology Program, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo 14049-900, Brazil; Corresponding author
Summary: Airway epithelial cells (AEC) infected with SARS-CoV-2 may drive the dysfunction of macrophages during COVID-19. We hypothesized that the direct interaction of AEC with macrophages mediated by CD95/CD95L or indirect interaction mediated by IL-6 signaling are key steps for the COVID-19 severe acute inflammation. The interaction of macrophages with apoptotic and infected AEC increased CD95 and CD163 expression, and induced macrophage death. Macrophages exposed to tracheal aspirate with high IL-6 levels from intubated patients with COVID-19 or to recombinant human IL-6 exhibited decreased HLA-DR expression, increased CD95 and CD163 expression and IL-1β production. IL-6 effects on macrophages were prevented by both CD95/CD95L antagonist and by IL-6 receptor antagonist and IL-6 or CD95 deficient mice showed significant reduction of acute pulmonary inflammation post-infection. Our findings show a non-canonical CD95L-CD95 pathway that simultaneously drives both macrophage activation and dysfunction and point to CD95/CD95L axis as therapeutic target.
