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

Area of Science:

• Immunology
• Cell Biology
• Virology

Background:

• Airway epithelial cells (AEC) infected with SARS-CoV-2 may contribute to macrophage dysfunction in COVID-19.
• Direct AEC-macrophage interaction via CD95/CD95L or indirect IL-6 signaling are hypothesized to drive severe acute inflammation.

Purpose of the Study:

• To investigate the role of CD95/CD95L and IL-6 signaling in SARS-CoV-2-induced macrophage dysfunction and pulmonary inflammation.

Main Methods:

• Co-culture of macrophages with apoptotic/infected AEC.
• Exposure of macrophages to tracheal aspirates or recombinant IL-6.
• Analysis of macrophage surface markers (CD95, CD163, HLA-DR) and cytokine production (IL-1β).
• Assessment of inflammation in IL-6 or CD95 deficient mice post-infection.

Main Results:

• Interaction with apoptotic/infected AEC increased CD95 and CD163 expression and induced macrophage death.
• IL-6 exposure decreased HLA-DR, increased CD95 and CD163, and promoted IL-1β production.
• CD95/CD95L and IL-6 receptor antagonists reversed IL-6 effects.
• IL-6 or CD95 deficient mice exhibited reduced pulmonary inflammation.

Conclusions:

• A non-canonical CD95L-CD95 pathway mediates both macrophage activation and dysfunction.
• The CD95/CD95L axis represents a potential therapeutic target for mitigating severe COVID-19-associated inflammation.