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Neutrophil-derived S100 calcium-binding proteins A8/A9 promote reticulated thrombocytosis and atherogenesis in diabetes


Platelets play a critical role in atherogenesis and thrombosis-mediated myocardial ischemia, processes that are accelerated in diabetes. Whether hyperglycemia promotes platelet production and whether enhanced platelet production contributes to enhanced atherothrombosis remains unknown. Here we found that in response to hyperglycemia, neutrophil-derived S100 calcium-binding proteins A8/A9 (S100A8/A9) interact with the receptor for advanced glycation end products (RAGE) on hepatic Kupffer cells, resulting in increased production of IL-6, a pleiotropic cytokine that is 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 cotransporter 2 inhibitor (dapagliflozin), depleting neutrophils or Kupffer cells, or inhibiting S100A8/A9 binding to RAGE (using paquinimod), all reduced diabetes-induced thrombocytosis. Inhibiting S100A8/A9 also decreased atherogenesis in diabetic mice. Finally, we found that patients with type 2 diabetes have reticulated thrombocytosis that correlates with glycated hemoglobin as well as increased plasma S100A8/A9 levels. These studies provide insights into the mechanisms that regulate platelet production and may aid in the development of strategies to improve on current antiplatelet therapies and to reduce cardiovascular disease risk in diabetes.

Type Journal
ISBN 1558-8238 (Electronic) 0021-9738 (Linking)
Authors Kraakman, M. J.; Lee, M. K.; Al-Sharea, A.; Dragoljevic, D.; Barrett, T. J.; Montenont, E.; Basu, D.; Heywood, S.; Kammoun, H. L.; Flynn, M.; Whillas, A.; Hanssen, N. M.; Febbraio, M. A.; Westein, E.; Fisher, E. A.; Chin-Dusting, J.; Cooper, M. E.; Berger, J. S.; Goldberg, I. J.; Nagareddy, P. R.; Murphy, A. J.
Responsible Garvan Author (missing name)
Published Date 2017-06-01
Published Volume 127
Published Issue 6
Published Pages 2133-2147
Status Published in-print
DOI 10.1172/JCI92450
URL link to publisher's version
OpenAccess link to author's accepted manuscript version