Hyperglycemia Induces Trained Immunity in Macrophages and Their Precursors and Promotes Atherosclerosis. Issue 12 (13th July 2021)

• Record Type: Journal Article
• 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.
• Is Part Of: Circulation. Volume 144:Issue 12(2021)
• Page Start: 961
• Page End: 982
• Publication Date: 2021-07-13
• Subjects: diabetes mellitus -- epigenetics -- glucose -- inflammation -- macrophages; Blood -- Circulation -- Periodicals; Cardiovascular system -- Periodicals; Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; Blood Circulation; Cardiovascular System; Vascular Diseases; 616.1
• DOI: 10.1161/CIRCULATIONAHA.120.046464
• Languages: English
• ISSNs: 0009-7322

Abstract

Abstract : Supplemental Digital Content is available in the text. Abstract : Background: Cardiovascular risk in diabetes remains elevated despite glucose-lowering therapies. We hypothesized that hyperglycemia induces trained immunity in macrophages, promoting persistent proatherogenic characteristics. Methods: 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. Results: 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. Conclusions: 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.