cGAS integrates Toll-like receptor signaling in platelets to promote thromboinflammation

Activation of TLR4, TLR1/2, and TLR5 in platelets triggers an mtDNA–cGAS–STING pathway that promotes platelet activation, including in endotoxemia.

• Why it matters: Thromboinflammation in sepsis involves platelet amplification of inflammation and coagulation, but how distinct innate signals converge on a shared platelet response is unclear.
• What they did: The study tested platelet-intrinsic cGAS-STING signaling using genetic cGAS deletion in an endotoxemia model, platelet transfer experiments, and mechanistic assays linking cytosolic mtDNA to MCU-dependent mitochondrial changes.
• The result: cGAS deletion reduced platelet activation, thrombocytopenia, pyroptosis, and early systemic inflammation, and platelet-intrinsic cGAS was sufficient to amplify in vivo responses; human platelet TLR1/2 effects required MCU and STING.

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