Abstract
Platelet-leukocyte interactions are important for innate immune responses, but also contribute to the pathogenesis of thrombotic disorders, such as deep vein thrombosis. How these interactions are manifest and how they influence leukocyte function remains poorly understood. Here, we demonstrate that binding to von Willebrand factor under flow through glycoprotein Ibα ‘primes’ platelets resulting in intracellular Ca2+ release and αIIbβ3 activation. This priming enables platelets to bind leukocytes via a mechanism that is largely independent of P-selectin, but that is inhibited by blocking αIIbβ3. We show that neutrophils and T-cells bind directly to activated αIIbβ3 under flow, identifying this platelet integrin as a novel leukocyte receptor. Binding of neutrophils to αIIbβ3 under flow causes rapid intracellular Ca2+ release, and initiates Ca2+- and NADPH oxidase-dependent signaling leading to production of neutrophil extracellular traps (NETs). NET production is itself dependent upon a mechanosensitive mechanism, as NETosis is markedly diminished if neutrophils are captured by αIIbβ3 under static conditions. Taken together, these data demonstrate a novel mechanism for platelet-neutrophil cross-talk and mechanosensitive NET production.