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...

Celý popis

Uloženo v:
Podrobná bibliografie
Vydáno v:Circulation (New York, N.Y.) Ročník 144; číslo 12; s. 961
Hlavní autoři: 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
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 21.09.2021
Témata:
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
On-line přístup:Zjistit podrobnosti o přístupu
Tagy: Přidat tag
Žádné tagy, Buďte první, kdo vytvoří štítek k tomuto záznamu!
Popis
Shrnutí: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.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1524-4539
1524-4539
DOI:10.1161/CIRCULATIONAHA.120.046464