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

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

iScience (2023-12-04)
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
ANOTACE

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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Phorbol 12-myristate 13-acetate, ≥99% (TLC), film or powder
Sigma-Aldrich
Fas/FasL Antagonist, Kp7-6, The Fas/FasL Antagonist, Kp7-6 controls the biological activity of Fas/FasL. This small molecule/inhibitor is primarily used for Cancer applications.