cGAS integrates Toll-like receptor signaling in platelets to promote thromboinflammation
Thromboinflammation is driven by innate immune signaling and promotes tissue injury during sepsis. Activation of platelets by bacterial products and alarmins amplifies inflammation, coagulation, and thrombotic dysfunction. However, the mechanisms by which these diverse inflammatory signals converge to elicit common platelet responses remain largely undefined. Mitochondria are key integrators of…
Thromboinflammation, a process that combines inflammation and blood clotting, contributes to tissue damage during infections like sepsis. Platelets, the tiniest blood cells, play a crucial role in amplifying this response. The precise mechanisms by which various inflammatory signals unite to trigger similar platelet reactions are still unclear.
Mitochondria, the powerhouses of cells, are crucial in integrating various stress responses. They can activate innate immune pathways by releasing mitochondrial DNA and engaging the cGAS sensor. We proposed that stimulation of innate immune receptors within platelets generates cGAS ligands, leading to a unified mechanism where multiple inflammatory cues converge on cGAS-STING signaling.
Our research confirmed that activation of TLR4, TLR1/2, and TLR5 in platelets activates a platelet-intrinsic mtDNA-cGAS-STING axis that enhances platelet activation. In an endotoxemia model, deleting cGAS reduced platelet activation, decreased platelet count, pyroptosis, and the initial systemic inflammatory response. Platelet transfer experiments showed that platelet-intrinsic cGAS alone can amplify inflammatory responses in the body.
Mechanistically, we found that cytosolic accumulation of mtDNA and activation of cGAS-STING signaling in platelets depend on mitochondrial calcium uniporter (MCU), mitochondrial membrane potential loss, and mitochondrial reactive oxygen species production. Unlike common platelet stimulants, cGAS-independent signaling did not induce significant cytosolic mtDNA accumulation.
This signaling pathway was similarly active in human platelets, where TLR1/2-mediated activation required MCU- and STING-dependent signaling, while responses to thrombin receptor-activating peptide and collagen-related peptide remained unchanged. In conclusion, cGAS acts as an intracellular integration point allowing different innate immune receptors to converge on a common platelet activation pathway by sensing mitochondria-derived DNA, enabling a swift platelet reaction to microbial components.
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