Abstract 38: Neutrophil-Derived S100a8 and S100a9 Promotes Reticulated Thrombocytosis and Atherogenesis in Diabetes

Platelets play a critical role in atherogenesis and thrombosis-mediated myocardial ischemia, processes that are accelerated in diabetes. It remains unknown if hyperglycemia promotes platelet production and whether this contributes to enhanced atherothrombosis. Here we show that in response to hyperglycemia, neutrophil-derived S100A8/A9 interacts with the receptor for advanced glycated end-products (RAGE) on hepatic Kupffer cells resulting in increased production of interleukin-6 (IL-6), a pleiotropic cytokine implicated in inflammatory thrombocytosis. IL-6 acts on hepatocytes to enhance the production of thrombopoietin, which in turn interacts with its cognate receptor, c-MPL on megakaryocytes and bone marrow progenitor cells to promote their expansion and proliferation resulting in reticulated thrombocytosis. Lowering blood glucose using a sodium-glucose co-transporter 2 inhibitor (dapagliflozin), depleting neutrophils/Kupffer cells or inhibiting S100A8/A9 binding to RAGE (paquinimod) all reduced diabetes-induced thrombocytosis. Inhibiting S100A8/A9 also decreased atherogenesis in diabetic mice. Finally, we show that patients with type 2 diabetes have reticulated thrombocytosis, which correlates with glycated hemoglobin, and also have increased plasma S100A8/A9 levels. These studies provide novel insights into the mechanisms that regulate platelet production and may help to develop strategies to improve on current antiplatelet therapies and to reduce cardiovascular disease risk in diabetes.