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 E Heywood, Helene L. Kammoun, Michelle Flynn, Alexandra Whillas, Nordin M J Hanssen, Mark A. Febbraio, Erik Westein, Edward Allen Fisher, Jaye Chin-Dusting, Mark E. Cooper, Jeffrey S. Berger, Ira Jay Goldberg, Prabhakara Reddy Nagareddy & 1 others Andrew J. Murphy

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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.

Original languageEnglish
Pages (from-to)2133-2147
Number of pages15
JournalJournal of Clinical Investigation
Volume127
Issue number6
DOIs
Publication statusPublished - 1 Jun 2017

Cite this

Kraakman, Michael J. ; Lee, Man K.S. ; Al-Sharea, Annas ; Dragoljevic, Dragana ; Barrett, Tessa J. ; Montenont, Emilie ; Basu, Debapriya ; Heywood, Sarah E ; Kammoun, Helene L. ; Flynn, Michelle ; Whillas, Alexandra ; Hanssen, Nordin M J ; Febbraio, Mark A. ; Westein, Erik ; Fisher, Edward Allen ; Chin-Dusting, Jaye ; Cooper, Mark E. ; Berger, Jeffrey S. ; Goldberg, Ira Jay ; Nagareddy, Prabhakara Reddy ; Murphy, Andrew J. / Neutrophil-derived S100 calcium-binding proteins A8/A9 promote reticulated thrombocytosis and atherogenesis in diabetes. In: Journal of Clinical Investigation. 2017 ; Vol. 127, No. 6. pp. 2133-2147.
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title = "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.",
author = "Kraakman, {Michael J.} and Lee, {Man K.S.} and Annas Al-Sharea and Dragana Dragoljevic and Barrett, {Tessa J.} and Emilie Montenont and Debapriya Basu and Heywood, {Sarah E} and Kammoun, {Helene L.} and Michelle Flynn and Alexandra Whillas and Hanssen, {Nordin M J} and Febbraio, {Mark A.} and Erik Westein and Fisher, {Edward Allen} and Jaye Chin-Dusting and Cooper, {Mark E.} and Berger, {Jeffrey S.} and Goldberg, {Ira Jay} and Nagareddy, {Prabhakara Reddy} and Murphy, {Andrew J.}",
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Kraakman, MJ, Lee, MKS, Al-Sharea, A, Dragoljevic, D, Barrett, TJ, Montenont, E, Basu, D, Heywood, SE, Kammoun, HL, Flynn, M, Whillas, A, Hanssen, NMJ, Febbraio, MA, Westein, E, Fisher, EA, Chin-Dusting, J, Cooper, ME, Berger, JS, Goldberg, IJ, Nagareddy, PR & Murphy, AJ 2017, 'Neutrophil-derived S100 calcium-binding proteins A8/A9 promote reticulated thrombocytosis and atherogenesis in diabetes', Journal of Clinical Investigation, vol. 127, no. 6, pp. 2133-2147. https://doi.org/10.1172/JCI92450

Neutrophil-derived S100 calcium-binding proteins A8/A9 promote reticulated thrombocytosis and atherogenesis in diabetes. / Kraakman, Michael J.; Lee, Man K.S.; Al-Sharea, Annas; Dragoljevic, Dragana; Barrett, Tessa J.; Montenont, Emilie; Basu, Debapriya; Heywood, Sarah E; Kammoun, Helene L.; Flynn, Michelle; Whillas, Alexandra; Hanssen, Nordin M J; Febbraio, Mark A.; Westein, Erik; Fisher, Edward Allen; Chin-Dusting, Jaye; Cooper, Mark E.; Berger, Jeffrey S.; Goldberg, Ira Jay; Nagareddy, Prabhakara Reddy; Murphy, Andrew J.

In: Journal of Clinical Investigation, Vol. 127, No. 6, 01.06.2017, p. 2133-2147.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Neutrophil-derived S100 calcium-binding proteins A8/A9 promote reticulated thrombocytosis and atherogenesis in diabetes

AU - Kraakman, Michael J.

AU - Lee, Man K.S.

AU - Al-Sharea, Annas

AU - Dragoljevic, Dragana

AU - Barrett, Tessa J.

AU - Montenont, Emilie

AU - Basu, Debapriya

AU - Heywood, Sarah E

AU - Kammoun, Helene L.

AU - Flynn, Michelle

AU - Whillas, Alexandra

AU - Hanssen, Nordin M J

AU - Febbraio, Mark A.

AU - Westein, Erik

AU - Fisher, Edward Allen

AU - Chin-Dusting, Jaye

AU - Cooper, Mark E.

AU - Berger, Jeffrey S.

AU - Goldberg, Ira Jay

AU - Nagareddy, Prabhakara Reddy

AU - Murphy, Andrew J.

PY - 2017/6/1

Y1 - 2017/6/1

N2 - 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.

AB - 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.

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DO - 10.1172/JCI92450

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JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

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