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AIRWAY EPITHELIAL CELLS AND MACROPHAGES TRIGGER IL-6-CD95/CD95L AXIS AND MEDIATE INITIAL IMMUNOPATHOLOGY OF COVID-19
Author
Fraga-Silva, Thais F C
Cipriano, Ualter G
Fumagalli, Marcilio J
Correa, Giseli F
Fuzo, Carlos A
Dos-Santos, Douglas
Mestriner, Fabiola L A C
Becari, Christiane
Carvalho, Andrea Teixeira
Coelho-Dos-Reis, Jordana
Menegueti, Mayra G
Figueiredo, Luiz T M
Cunha, Larissa Dias
Martins Filho, Olindo Assis
Dias-Baruffi, Marcelo
Auxiliadora-Martins, Maria
Tostes, Rita C
Bonato, Vania L D
Cipriano, Ualter G
Fumagalli, Marcilio J
Correa, Giseli F
Fuzo, Carlos A
Dos-Santos, Douglas
Mestriner, Fabiola L A C
Becari, Christiane
Carvalho, Andrea Teixeira
Coelho-Dos-Reis, Jordana
Menegueti, Mayra G
Figueiredo, Luiz T M
Cunha, Larissa Dias
Martins Filho, Olindo Assis
Dias-Baruffi, Marcelo
Auxiliadora-Martins, Maria
Tostes, Rita C
Bonato, Vania L D
Affilliation
Department of Biochemistry and Immunology. Ribeirao Preto Medical School. University of Sao Paulo. Ribeirao Preto, SP, Brazil.
Basic and Applied Immunology Program. Ribeirao Preto Medical School. University of Sao Paulo. Ribeirao Preto, SP, Brazil.
Basic and Applied Immunology Program. Ribeirao Preto Medical School. University of Sao Paulo. Ribeirao Preto, SP, Brazil.
Basic and Applied Immunology Program. Ribeirao Preto Medical School. University of Sao Paulo. Ribeirao Preto, SP, Brazil.
Department of Clinical Analysis, Toxicology and Food Sciences. School of Pharmaceutical Sciences of Ribeirão Preto. University of Sao Paulo. Ribeirao Preto, SP, Brazil.
Department of Cell Biology. Ribeirao Preto Medical School. University of Sao Paulo. Ribeirao Preto, SP, Brazil.
Department of Surgery and Anatomy. Ribeirao Preto Medical School. University of Sao Paulo. Ribeirao Preto, SP, Brazil.
Department of Surgery and Anatomy. Ribeirao Preto Medical School. University of Sao Paulo. Ribeirao Preto, SP, Brazil.
René Rachou Institute. Oswaldo Cruz Foundation. Belo Horizonte, MG, Brazil.
Department of Microbiology. Biological Science Institute. Federal University of Minas Gerais. Belo Horizonte, MG, Brazil.
Department of General and Specialized Nursing, Ribeirao Preto Nurse School, University of Sao Paulo. Ribeirao Preto, SP, Brazil.
Basic and Applied Immunology Program. Ribeirao Preto Medical School. University of Sao Paulo. Ribeirao Preto, SP, Brazil/Virology Research Center. Ribeirao Preto Medical School. University of Sao Paulo. Ribeirao Preto, SP, Brazil.
Department of Cell Biology. Ribeirao Preto Medical School. University of Sao Paulo. Ribeirao Preto, SP, Brazil.
René Rachou Institute. Oswaldo Cruz Foundation. Belo Horizonte, MG, Brazil
Department of Clinical Analysis, Toxicology and Food Sciences. School of Pharmaceutical Sciences of Ribeirão Preto. University of Sao Paulo. Ribeirao Preto, SP, Brazil.
Department of Surgery and Anatomy. Ribeirao Preto Medical School. University of Sao Paulo. Ribeirao Preto, SP, Brazil.
Department of Pharmacology. Ribeirao Preto Medical School. University of Sao Paulo. Ribeirao Preto, SP, Brazil.
Department of Biochemistry and Immunology. Ribeirao Preto Medical School. University of Sao Paulo. Ribeirao Preto, SP, Brazil/Basic and Applied Immunology Program. Ribeirao Preto Medical School. University of Sao Paulo. Ribeirao Preto, SP, Brazil.
Basic and Applied Immunology Program. Ribeirao Preto Medical School. University of Sao Paulo. Ribeirao Preto, SP, Brazil.
Basic and Applied Immunology Program. Ribeirao Preto Medical School. University of Sao Paulo. Ribeirao Preto, SP, Brazil.
Basic and Applied Immunology Program. Ribeirao Preto Medical School. University of Sao Paulo. Ribeirao Preto, SP, Brazil.
Department of Clinical Analysis, Toxicology and Food Sciences. School of Pharmaceutical Sciences of Ribeirão Preto. University of Sao Paulo. Ribeirao Preto, SP, Brazil.
Department of Cell Biology. Ribeirao Preto Medical School. University of Sao Paulo. Ribeirao Preto, SP, Brazil.
Department of Surgery and Anatomy. Ribeirao Preto Medical School. University of Sao Paulo. Ribeirao Preto, SP, Brazil.
Department of Surgery and Anatomy. Ribeirao Preto Medical School. University of Sao Paulo. Ribeirao Preto, SP, Brazil.
René Rachou Institute. Oswaldo Cruz Foundation. Belo Horizonte, MG, Brazil.
Department of Microbiology. Biological Science Institute. Federal University of Minas Gerais. Belo Horizonte, MG, Brazil.
Department of General and Specialized Nursing, Ribeirao Preto Nurse School, University of Sao Paulo. Ribeirao Preto, SP, Brazil.
Basic and Applied Immunology Program. Ribeirao Preto Medical School. University of Sao Paulo. Ribeirao Preto, SP, Brazil/Virology Research Center. Ribeirao Preto Medical School. University of Sao Paulo. Ribeirao Preto, SP, Brazil.
Department of Cell Biology. Ribeirao Preto Medical School. University of Sao Paulo. Ribeirao Preto, SP, Brazil.
René Rachou Institute. Oswaldo Cruz Foundation. Belo Horizonte, MG, Brazil
Department of Clinical Analysis, Toxicology and Food Sciences. School of Pharmaceutical Sciences of Ribeirão Preto. University of Sao Paulo. Ribeirao Preto, SP, Brazil.
Department of Surgery and Anatomy. Ribeirao Preto Medical School. University of Sao Paulo. Ribeirao Preto, SP, Brazil.
Department of Pharmacology. Ribeirao Preto Medical School. University of Sao Paulo. Ribeirao Preto, SP, Brazil.
Department of Biochemistry and Immunology. Ribeirao Preto Medical School. University of Sao Paulo. Ribeirao Preto, SP, Brazil/Basic and Applied Immunology Program. Ribeirao Preto Medical School. University of Sao Paulo. Ribeirao Preto, SP, 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.
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