Neutrophil-derived S100 calcium-binding proteins A8/A9 promote reticulated thrombocytosis and atherogenesis in diabetes
Michael J. Kraakman, … , Prabhakara R. Nagareddy, Andrew J. Murphy
Michael J. Kraakman, … , Prabhakara R. Nagareddy, Andrew J. Murphy
Published May 15, 2017
Citation Information: J Clin Invest. 2017;127(6):2133-2147. https://doi.org/10.1172/JCI92450.
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Research Article Inflammation Vascular biology

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

Abstract

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.

Authors

Michael J. Kraakman, Man K.S. Lee, Annas Al-Sharea, Dragana Dragoljevic, Tessa J. Barrett, Emilie Montenont, Debapriya Basu, Sarah Heywood, Helene L. Kammoun, Michelle Flynn, Alexandra Whillas, Nordin M.J. Hanssen, Mark A. Febbraio, Erik Westein, Edward A. Fisher, Jaye Chin-Dusting, Mark E. Cooper, Jeffrey S. Berger, Ira J. Goldberg, Prabhakara R. Nagareddy, Andrew J. Murphy

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Figure 4

IL-6 drives reticulated thrombocytosis in diabetes.

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IL-6 drives reticulated thrombocytosis in diabetes. (A) Experimental ove...
(A) Experimental overview: C57BL/6 WT recipient mice were transplanted with BM from WT or Il6–/– donor mice, and after 5 weeks a subset of mice were rendered diabetic with STZ. After 4 weeks the mice were analyzed. (B) Blood glucose levels. (C) Percentage of Kupffer cells in the liver was quantified by flow cytometry. (D and E) Percentage (D) and numbers (E) of circulating reticulated platelets. TO, thiazole orange. (F and G) Abundance (F) and proliferation (G) of MkPs in the BM were quantified by flow cytometry. n = 5 WT groups, n = 6 Il6–/– controls, and n = 10 Il6–/– STZ. *P < 0.05 for disease effect, #P < 0.05 for genotype effect. All data represent the mean ± SEM. P values were obtained using a 2-way ANOVA.