Hyperglycemia Induces Trained Immunity in Macrophages and Their Precursors and Promotes Atherosclerosis

Cardiovascular risk in diabetes remains elevated despite glucose-lowering therapies. We hypothesized that hyperglycemia induces trained immunity in macrophages, promoting persistent proatherogenic characteristics. Bone marrow-derived macrophages from control mice and mice with diabetes were grown in...

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Published in:	Circulation (New York, N.Y.) Vol. 144; no. 12; p. 961
Main Authors:	Edgar, Laurienne, Akbar, Naveed, Braithwaite, Adam T, Krausgruber, Thomas, Gallart-Ayala, Héctor, Bailey, Jade, Corbin, Alastair L, Khoyratty, Tariq E, Chai, Joshua T, Alkhalil, Mohammad, Rendeiro, André F, Ziberna, Klemen, Arya, Ritu, Cahill, Thomas J, Bock, Christoph, Laurencikiene, Jurga, Crabtree, Mark J, Lemieux, Madeleine E, Riksen, Niels P, Netea, Mihai G, Wheelock, Craig E, Channon, Keith M, Rydén, Mikael, Udalova, Irina A, Carnicer, Ricardo, Choudhury, Robin P
Format:	Journal Article
Language:	English
Published:	United States 21.09.2021
Subjects:	Animals Atherosclerosis - immunology Atherosclerosis - pathology Cells, Cultured Diabetes Mellitus, Experimental - immunology Diabetes Mellitus, Experimental - pathology Endarterectomy, Carotid Humans Hyperglycemia - immunology Hyperglycemia - pathology Immunity, Cellular - immunology Leukocytes, Mononuclear - immunology Leukocytes, Mononuclear - pathology Macrophages - immunology Macrophages - pathology Mice Mice, 129 Strain Mice, Transgenic glucose macrophages diabetes mellitus inflammation epigenetics
ISSN:	1524-4539, 1524-4539
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Abstract	Cardiovascular risk in diabetes remains elevated despite glucose-lowering therapies. We hypothesized that hyperglycemia induces trained immunity in macrophages, promoting persistent proatherogenic characteristics. Bone marrow-derived macrophages from control mice and mice with diabetes were grown in physiological glucose (5 mmol/L) and subjected to RNA sequencing (n=6), assay for transposase accessible chromatin sequencing (n=6), and chromatin immunoprecipitation sequencing (n=6) for determination of hyperglycemia-induced trained immunity. Bone marrow transplantation from mice with (n=9) or without (n=6) diabetes into (normoglycemic) mice was used to assess its functional significance in vivo. Evidence of hyperglycemia-induced trained immunity was sought in human peripheral blood mononuclear cells from patients with diabetes (n=8) compared with control subjects (n=16) and in human atherosclerotic plaque macrophages excised by laser capture microdissection. In macrophages, high extracellular glucose promoted proinflammatory gene expression and proatherogenic functional characteristics through glycolysis-dependent mechanisms. Bone marrow-derived macrophages from diabetic mice retained these characteristics, even when cultured in physiological glucose, indicating hyperglycemia-induced trained immunity. Bone marrow transplantation from diabetic mice into (normoglycemic) mice increased aortic root atherosclerosis, confirming a disease-relevant and persistent form of trained innate immunity. Integrated assay for transposase accessible chromatin, chromatin immunoprecipitation, and RNA sequencing analyses of hematopoietic stem cells and bone marrow-derived macrophages revealed a proinflammatory priming effect in diabetes. The pattern of open chromatin implicated transcription factor Runt-related transcription factor 1 (Runx1). Similarly, transcriptomes of atherosclerotic plaque macrophages and peripheral leukocytes in patients with type 2 diabetes were enriched for Runx1 targets, consistent with a potential role in human disease. Pharmacological inhibition of Runx1 in vitro inhibited the trained phenotype. Hyperglycemia-induced trained immunity may explain why targeting elevated glucose is ineffective in reducing macrovascular risk in diabetes and suggests new targets for disease prevention and therapy.
AbstractList	Cardiovascular risk in diabetes remains elevated despite glucose-lowering therapies. We hypothesized that hyperglycemia induces trained immunity in macrophages, promoting persistent proatherogenic characteristics.BACKGROUNDCardiovascular risk in diabetes remains elevated despite glucose-lowering therapies. We hypothesized that hyperglycemia induces trained immunity in macrophages, promoting persistent proatherogenic characteristics.Bone marrow-derived macrophages from control mice and mice with diabetes were grown in physiological glucose (5 mmol/L) and subjected to RNA sequencing (n=6), assay for transposase accessible chromatin sequencing (n=6), and chromatin immunoprecipitation sequencing (n=6) for determination of hyperglycemia-induced trained immunity. Bone marrow transplantation from mice with (n=9) or without (n=6) diabetes into (normoglycemic) Ldlr-/- mice was used to assess its functional significance in vivo. Evidence of hyperglycemia-induced trained immunity was sought in human peripheral blood mononuclear cells from patients with diabetes (n=8) compared with control subjects (n=16) and in human atherosclerotic plaque macrophages excised by laser capture microdissection.METHODSBone marrow-derived macrophages from control mice and mice with diabetes were grown in physiological glucose (5 mmol/L) and subjected to RNA sequencing (n=6), assay for transposase accessible chromatin sequencing (n=6), and chromatin immunoprecipitation sequencing (n=6) for determination of hyperglycemia-induced trained immunity. Bone marrow transplantation from mice with (n=9) or without (n=6) diabetes into (normoglycemic) Ldlr-/- mice was used to assess its functional significance in vivo. Evidence of hyperglycemia-induced trained immunity was sought in human peripheral blood mononuclear cells from patients with diabetes (n=8) compared with control subjects (n=16) and in human atherosclerotic plaque macrophages excised by laser capture microdissection.In macrophages, high extracellular glucose promoted proinflammatory gene expression and proatherogenic functional characteristics through glycolysis-dependent mechanisms. Bone marrow-derived macrophages from diabetic mice retained these characteristics, even when cultured in physiological glucose, indicating hyperglycemia-induced trained immunity. Bone marrow transplantation from diabetic mice into (normoglycemic) Ldlr-/- mice increased aortic root atherosclerosis, confirming a disease-relevant and persistent form of trained innate immunity. Integrated assay for transposase accessible chromatin, chromatin immunoprecipitation, and RNA sequencing analyses of hematopoietic stem cells and bone marrow-derived macrophages revealed a proinflammatory priming effect in diabetes. The pattern of open chromatin implicated transcription factor Runt-related transcription factor 1 (Runx1). Similarly, transcriptomes of atherosclerotic plaque macrophages and peripheral leukocytes in patients with type 2 diabetes were enriched for Runx1 targets, consistent with a potential role in human disease. Pharmacological inhibition of Runx1 in vitro inhibited the trained phenotype.RESULTSIn macrophages, high extracellular glucose promoted proinflammatory gene expression and proatherogenic functional characteristics through glycolysis-dependent mechanisms. Bone marrow-derived macrophages from diabetic mice retained these characteristics, even when cultured in physiological glucose, indicating hyperglycemia-induced trained immunity. Bone marrow transplantation from diabetic mice into (normoglycemic) Ldlr-/- mice increased aortic root atherosclerosis, confirming a disease-relevant and persistent form of trained innate immunity. Integrated assay for transposase accessible chromatin, chromatin immunoprecipitation, and RNA sequencing analyses of hematopoietic stem cells and bone marrow-derived macrophages revealed a proinflammatory priming effect in diabetes. The pattern of open chromatin implicated transcription factor Runt-related transcription factor 1 (Runx1). Similarly, transcriptomes of atherosclerotic plaque macrophages and peripheral leukocytes in patients with type 2 diabetes were enriched for Runx1 targets, consistent with a potential role in human disease. Pharmacological inhibition of Runx1 in vitro inhibited the trained phenotype.Hyperglycemia-induced trained immunity may explain why targeting elevated glucose is ineffective in reducing macrovascular risk in diabetes and suggests new targets for disease prevention and therapy.CONCLUSIONSHyperglycemia-induced trained immunity may explain why targeting elevated glucose is ineffective in reducing macrovascular risk in diabetes and suggests new targets for disease prevention and therapy. Cardiovascular risk in diabetes remains elevated despite glucose-lowering therapies. We hypothesized that hyperglycemia induces trained immunity in macrophages, promoting persistent proatherogenic characteristics. Bone marrow-derived macrophages from control mice and mice with diabetes were grown in physiological glucose (5 mmol/L) and subjected to RNA sequencing (n=6), assay for transposase accessible chromatin sequencing (n=6), and chromatin immunoprecipitation sequencing (n=6) for determination of hyperglycemia-induced trained immunity. Bone marrow transplantation from mice with (n=9) or without (n=6) diabetes into (normoglycemic) mice was used to assess its functional significance in vivo. Evidence of hyperglycemia-induced trained immunity was sought in human peripheral blood mononuclear cells from patients with diabetes (n=8) compared with control subjects (n=16) and in human atherosclerotic plaque macrophages excised by laser capture microdissection. In macrophages, high extracellular glucose promoted proinflammatory gene expression and proatherogenic functional characteristics through glycolysis-dependent mechanisms. Bone marrow-derived macrophages from diabetic mice retained these characteristics, even when cultured in physiological glucose, indicating hyperglycemia-induced trained immunity. Bone marrow transplantation from diabetic mice into (normoglycemic) mice increased aortic root atherosclerosis, confirming a disease-relevant and persistent form of trained innate immunity. Integrated assay for transposase accessible chromatin, chromatin immunoprecipitation, and RNA sequencing analyses of hematopoietic stem cells and bone marrow-derived macrophages revealed a proinflammatory priming effect in diabetes. The pattern of open chromatin implicated transcription factor Runt-related transcription factor 1 (Runx1). Similarly, transcriptomes of atherosclerotic plaque macrophages and peripheral leukocytes in patients with type 2 diabetes were enriched for Runx1 targets, consistent with a potential role in human disease. Pharmacological inhibition of Runx1 in vitro inhibited the trained phenotype. Hyperglycemia-induced trained immunity may explain why targeting elevated glucose is ineffective in reducing macrovascular risk in diabetes and suggests new targets for disease prevention and therapy.
Author	Netea, Mihai G Carnicer, Ricardo Choudhury, Robin P Bock, Christoph Cahill, Thomas J Channon, Keith M Crabtree, Mark J Gallart-Ayala, Héctor Riksen, Niels P Bailey, Jade Edgar, Laurienne Alkhalil, Mohammad Akbar, Naveed Rendeiro, André F Ziberna, Klemen Braithwaite, Adam T Lemieux, Madeleine E Krausgruber, Thomas Udalova, Irina A Arya, Ritu Laurencikiene, Jurga Rydén, Mikael Chai, Joshua T Wheelock, Craig E Corbin, Alastair L Khoyratty, Tariq E
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Ziberna fullname: Ziberna, Klemen organization: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, UK (L.E., N.A., A.T.B., J.B., J.T.C., M.A., K.Z., R.A., T.J.C., M.J.C., K.M.C., R.C., R.P.C.) – sequence: 13 givenname: Ritu surname: Arya fullname: Arya, Ritu organization: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, UK (L.E., N.A., A.T.B., J.B., J.T.C., M.A., K.Z., R.A., T.J.C., M.J.C., K.M.C., R.C., R.P.C.) – sequence: 14 givenname: Thomas J surname: Cahill fullname: Cahill, Thomas J organization: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, UK (L.E., N.A., A.T.B., J.B., J.T.C., M.A., K.Z., R.A., T.J.C., M.J.C., K.M.C., R.C., R.P.C.) – sequence: 15 givenname: Christoph orcidid: 0000-0001-6091-3088 surname: Bock fullname: Bock, Christoph organization: Institute of Artificial Intelligence and Decision Support, Center for Medical Statistics, 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Netea fullname: Netea, Mihai G organization: Department for Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Germany (M.G.N.) – sequence: 21 givenname: Craig E surname: Wheelock fullname: Wheelock, Craig E organization: Department of Respiratory Medicine and Allergy (H.G.-A., C.E.W.), Karolinska University Hospital, Stockholm, Sweden – sequence: 22 givenname: Keith M surname: Channon fullname: Channon, Keith M organization: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, UK (L.E., N.A., A.T.B., J.B., J.T.C., M.A., K.Z., R.A., T.J.C., M.J.C., K.M.C., R.C., R.P.C.) – sequence: 23 givenname: Mikael surname: Rydén fullname: Rydén, Mikael organization: Department of Medicine (H7) (J.L., M.R.), Karolinska University Hospital, Stockholm, Sweden – sequence: 24 givenname: Irina A surname: Udalova fullname: Udalova, Irina A organization: The Kennedy Institute of Rheumatology, University of Oxford, UK 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References	34312499 - Nat Rev Cardiol. 2021 Oct;18(10):687. doi: 10.1038/s41569-021-00606-4.
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Snippet	Cardiovascular risk in diabetes remains elevated despite glucose-lowering therapies. We hypothesized that hyperglycemia induces trained immunity in...
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SubjectTerms	Animals Atherosclerosis - immunology Atherosclerosis - pathology Cells, Cultured Diabetes Mellitus, Experimental - immunology Diabetes Mellitus, Experimental - pathology Endarterectomy, Carotid Humans Hyperglycemia - immunology Hyperglycemia - pathology Immunity, Cellular - immunology Leukocytes, Mononuclear - immunology Leukocytes, Mononuclear - pathology Macrophages - immunology Macrophages - pathology Mice Mice, 129 Strain Mice, Transgenic
Title	Hyperglycemia Induces Trained Immunity in Macrophages and Their Precursors and Promotes Atherosclerosis
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