Platelet mTOR Is a Regulator of Sterile Immunothrombosis.

backgroundImmunothrombosis entails a tight interplay between thrombotic and inflammatory pathways and plays a pathological role in ischemic stroke and venous thrombosis. mTOR (mechanistic target of rapamycin) is a canonical serine/threonine kinase and is involved in platelet signaling and thrombus stabilization in vitro. Activation of platelet mTOR is upregulated in aging and inflammatory disorders. However, its role in vivo is poorly understood.

methodsWe used mice specifically lacking mTOR in platelets and assessed platelet activation and platelet-leukocyte interactions in response to platelet agonists. In addition, we examined the role of platelet mTOR in models of hemostasis, thrombosis, inflammatory bleeding, and sterile immunothrombosis, including ischemic stroke and venous thrombosis.

resultsPlatelets lacking mTOR had a small activation defect and had lower procoagulant potential. In the absence of mTOR, activated platelets interacted less with monocytes and neutrophils. In addition, platelet mTOR regulated platelet-mediated neutrophil activation. Platelet cytoplasmic calcium flux was similar in the presence and absence of mTOR, whereas clot retraction was reduced in the absence of platelet mTOR, suggesting a role for mTOR in selectively regulating Rac1 (Ras-related C3 botulinum toxin substrate 1)-dependent pathways involved in sustained platelet function. In vivo, the absence of platelet mTOR did not impact hemostasis, inflammatory bleeding in the lung and skin, or FeCl

conclusionsPlatelet mTOR is a critical mediator of sterile immunothrombosis, although it is dispensable for hemostasis in mice. The immunothrombotic-specific effects of mTOR make it an attractive therapeutic target with a good safety profile.