Platelet Endocytosis in Innate Immunity

Platelets are capable of many cellular processes (i.e., RNA splicing, translation, glycosylation, endocytosis); however, their effects on function is often unclear. As circulating sentries, platelets sample the vasculature via endocytosis. We show that pathogen endocytosis induces immuno-activation of platelets, which could explain the increased cardiovascular risks associated with persistent infections, e.g., HIV. In this application, we build on our novel findings, hypothesizing that platelet endocytosis is critical for innate immunity. To test this hypothesis, we focus on how platelet endocytosis facilitates Toll-like Receptor (TLR)-based signaling. Using novel, genetically-altered mice (Arf6-/-, VAMP-3-/-, and Syntaxin-2/4-/-), which are defective at different steps, we will address the roles, routes, and mechanisms of platelet endocytosis in two specific aims: Aim 1. Determine the effects of defective platelet endocytosis on innate immune responses; Aim 2. Determine the mechanisms and routes of the platelet endocytic system. Our proposal advances platelets as “active” monitors of the vasculature, continuously interacting with their environment while circulating and during thrombosis. In our view, platelets use endocytosis to continuously sample their microenvironment and, through endocytic trafficking, deliver cues that affect how platelets respond to what they detect. Our work will yield insights into platelet function during thrombosis and during systemic infections, thus reshaping anti-thrombotic therapies. Finally, understanding platelet endocytosis will uncover strategies to target platelets or load them with therapeutics for CVD.