STING activation in platelets aggravates septic thrombosis by enhancing platelet activation and granule secretion

Sepsis is a dysregulated inflammatory consequence of systemic infection. As a result, excessive platelet acti-vation leads to thrombosis and coagulopathy, but we currently lack sufficient understanding of these pro-cesses. Here, using the cecal ligation and puncture (CLP) model of sepsis, we observed septic thrombosis and neutrophil extracellular trap formation (NETosis) within the mouse vasculature by intravital microscopy. STING activation in platelets was a critical driver of sepsis-induced pathology. Platelet-specific STING defi-ciency suppressed platelet activation and granule secretion, which alleviated sepsis-induced intravascular thrombosis and NETosis in mice. Mechanistically, sepsis-derived cGAMP promoted the binding of STING to STXBP2, the assembly of SNARE complex, granule secretion, and subsequent septic thrombosis, which probably depended on the palmitoylation of STING. We generated a peptide, C-ST5, to block STING binding to STXBP2. Septic mice treated with C-ST5 showed reduced thrombosis. Overall, platelet activation via STING reveals a potential strategy for limiting life-threatening sepsis-mediated coagulopathy.

Automated summary

Sepsis is a dysregulated inflammatory response caused by systemic infection, leading to excessive platelet activation and coagulation dysfunction. Through the use of a sepsis mouse model, researchers observed thrombosis and NETosis in the vasculature, triggered by STING activation in platelets. Platelet-specific STING deficiency reduced platelet activation and granule secretion, resulting in reduced thrombosis in septic mice. Mechanistically, sepsis-derived cGAMP promoted STING binding to STXBP2, leading to granule secretion and subsequent thrombosis, which may rely on STING palmitoylation. The peptide C-ST5, designed to block STING binding to STXBP2, showed promise in reducing thrombosis in septic mice. In conclusion, targeting platelet activation through STING activation provides a potential strategy for mitigating sepsis-induced coagulopathy.