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 Dias Cunha; Olindo A Martins-Filho; Marcelo Dias-Baruffi; Maria Auxiliadora-Martins; Rita C Tostes; Vania L D Bonato

doi:10.1016/j.isci.2023.108366

Airway epithelial cells and macrophages trigger IL-6-CD95/CD95L axis and mediate initial immunopathology of COVID-19

iScience. 2023 Oct 31;26(12):108366. doi: 10.1016/j.isci.2023.108366. eCollection 2023 Dec 15.

Authors

Thais F C Fraga-Silva¹, Ualter G Cipriano², Marcilio J Fumagalli², Giseli F Correa², Carlos A Fuzo³, Douglas Dos-Santos⁴, Fabiola L A C Mestriner⁵, Christiane Becari⁵, Andrea Teixeira-Carvalho⁶, Jordana Coelho-Dos-Reis⁷, Mayra G Menegueti⁸, Luiz T M Figueiredo^{2

9}, Larissa Dias Cunha⁴, Olindo A Martins-Filho⁶, Marcelo Dias-Baruffi³, Maria Auxiliadora-Martins⁵, Rita C Tostes¹⁰, Vania L D Bonato^{1

2}

Affiliations

¹ Department of Biochemistry and Immunology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo 14049-900, Brazil.
² Basic and Applied Immunology Program, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo 14049-900, Brazil.
³ 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.
⁴ Department of Cell Biology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo 14049-900, Brazil.
⁵ Department of Surgery and Anatomy, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo 14049-900, Brazil.
⁶ René Rachou Institute, Oswaldo Cruz Foundation, FIOCRUZ-Minas, Belo Horizonte, Minas Gerais 30190-009, Brazil.
⁷ Department of Microbiology, Biological Science Institute, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil.
⁸ Department of General and Specialized Nursing, Ribeirao Preto Nurse School, University of Sao Paulo, Ribeirao Preto, Sao Paulo 14049-900, Brazil.
⁹ Virology Research Center, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo 14049-900, Brazil.
¹⁰ Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo 14049-900, Brazil.

Abstract

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.

Keywords: Components of the immune system; Virology.