Neutrophil-derived S100 calcium-binding proteins A8/A9 promote reticulated thrombocytosis and atherogenesis in diabetes
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
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
View: Text | PDF
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

×

Figure 8

Blocking S100A8/A9 with ABR-215757 decreases atherogenesis in diabetic mice.

Options: View larger image (or click on image) Download as PowerPoint
Blocking S100A8/A9 with ABR-215757 decreases atherogenesis in diabetic m...
(A) Experimental overview: 8-week-old Apoe–/– mice were divided into 3 groups, vehicle (Cont), vehicle diabetic (STZ), and ABR-215757 diabetic (STZ+ABR; 10 mg/kg/d in drinking water), and fed a chow diet for 12 weeks. (B and C) Blood glucose levels (B) and plasma cholesterol levels (C). (D–G) Circulating reticulated platelets (D), Kupffer cells (E), Kupffer cell IL-6 expression (F), and BM MkPs (G) were measured by flow cytometry. (H) Quantification of mean lesion size. (I and J) Macrophage abundance was assessed by area of CD68+ regions (I) and lipid content by Oil Red O+ area (J). (K) Acellular regions were identified in H&E stain lesions (see arrows). (L) Percentage collagen content in the lesions was assessed by Picrosirius red staining and visualized under polarizing light. n = 9 control and STZ and n = 10 STZ+ABR. *P < 0.05 vs. WT (B and C), vs. all groups (D–G), or as indicated by lines (H–L). All data represent the mean ± SEM. P values were obtained using a 1-way ANOVA. Scale bars: 100 μm.