Grant: Travel Awards - Institute Community Support

PURPOSE: Proper function of blood cells is essential for protection against infectious disease and maintaining human health. During the onset of infection or following injury, white blood cells and platelets release signaling molecules known as cytokines, which orchestrate a protective inflammatory response. When cytokine release is de-regulated, excessive inflammation results that causes cell and tissue death and loss of function. In addition to regulating blood coagulation (clotting), platelets are emerging as pivotal components of the host inflammatory response. Notably, platelets are an important source of transforming growth factor beta 1 (TGF-B1), a cytokine that regulates wound healing, inflammation and cell-mediated immunity. The mechanisms underlying cytokine secretion from platelets are undefined but likely involve the structural framework of the cell (cytoskeleton). The Wiskott-Aldrich Syndrome protein (WASp) controls the actin cytoskeleton in white blood cells but has other function(s) in platelets. We hypothesized that WASp may control the release of TGF-B1 from platelets. RESULTS: Upon activation, WASp-deficient platelets released more TGF-B1 than normal (wild-type) platelets. Similarly, blocking WASp function with a chemical inhibitor augmented TGF-B1 release in human platelets. Chemical disruption of the actin cytoskeleton also increased TGF-B1 release, but this was independent of WASp function. CONCLUSION: WASp function restricts TGF-B1 secretion from platelets independently of the actin cytoskeleton. IMPACT: Identifying the biochemical mechanisms of cytokine secretion will improve our understanding of platelets and their role in the host inflammatory response.