Interferon-γ primes macrophages for pathogen ligand-induced killing via a caspase-8 and mitochondrial cell death...

Area of Science:

• Immunology
• Cell Biology
• Pathogen Infection

Background:

• Cell death is a critical component of the host response to pathogen infections.
• Macrophages are key immune cells that play a role in pathogen clearance and inflammation.
• Interferon-gamma (IFNγ) is a cytokine that modulates immune cell function.

Purpose of the Study:

• To investigate the mechanisms by which IFNγ sensitizes macrophages to Toll-like receptor (TLR)-induced death.
• To elucidate the role of specific signaling molecules, including caspase-8 and inducible nitric oxide synthase (iNOS), in this process.
• To determine the relevance of these findings in the context of SARS-CoV-2 infection and other inflammatory conditions.

Main Methods:

• Utilized macrophage cell cultures and in vivo mouse models.
• Investigated the roles of IFNγ, TLRs, death ligands, caspase-8, BAX, BAK, BID, iNOS, A1, and MCL-1 in macrophage death signaling.
• Assessed the impact of iNOS and caspase-8 deletion on SARS-CoV-2-induced disease and hemophagocytic lymphohistiocytosis models.

Main Results:

• IFNγ primes macrophages for TLR-induced death, dependent on macrophage-intrinsic death ligands and caspase-8 activity.
• Caspase-8 triggers mitochondrial apoptotic effectors BAX and BAK, independent of BID, by reducing BCL-2 transcription and increasing iNOS.
• iNOS licenses caspase-8 activity and reduces BAX/BAK inhibitors (A1, MCL-1), facilitating macrophage death; iNOS or caspase-8 deletion limits SARS-CoV-2 disease in mice.

Conclusions:

• iNOS selectively licenses programmed cell death in macrophages.
• This mechanism highlights the role of nitric oxide in modulating disease severity in SARS-CoV-2 infection and other iNOS-associated inflammatory conditions.
• Caspase-8 can induce lethality independent of iNOS in hemophagocytic lymphohistiocytosis models.