STING agonists trigger monocyte death via apoptosis, pyroptosis, caspase-8 activation and mitochondrial dysfunction

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• The cGAS-STING pathway senses cytoplasmic DNA, initiating immune responses.
• STING activation in monocytes triggers regulated cell death (RCD) linked to cytokine release.

Purpose of the Study:

• To elucidate the mechanisms of STING agonist-induced RCD in human monocytes.
• To characterize the interplay between apoptosis, pyroptosis, and necroptosis in this context.

Main Methods:

• Analysis of caspase activation (caspase-9, -8, -3/7, -1).
• Assessment of pyroptosis markers (cleaved gasdermin-D, IL-1β, IL-18).
• Investigation of mitochondrial function and RIPK1 involvement.

Main Results:

• STING agonist-induced RCD involves both apoptotic and pyroptotic pathways.
• Necroptosis is suppressed via RIPK1 cleavage by caspase-8.
• Mitochondrial dysfunction precedes caspase activation, suggesting a key role in RCD initiation.

Conclusions:

• A novel form of RCD, termed 'pyroptotic apoptosis', is identified in monocytes.
• Mitochondrial disruption is central to cGAS-STING pathway-mediated cell death.
• Findings offer new insights into cGAS-STING signaling outcomes in monocytes.