| Title: |
Hyperglycemia induces trained immunity in macrophages and their precursors and promotes atherosclerosis |
| Authors: |
Edgar, L; Akbar, N; Braithwaite, AT; Krausgruber, T; Gallart-Ayala, H; Bailey, J; Corbin, AL; Khoyratty, TE; Chai, JT; Alkhalil, M; Rendeiro, AF; Ziberna, K; Arya, R; Cahill, TJ; Bock, C; Laurencikiene, J; Crabtree, MJ; Lemieux, ME; Riksen, NP; Netea, MG; Wheelock, CE; Channon, KM; Rydén, M; Udalova, IA; Carnicer, R; Choudhury, RP |
| Publisher Information: |
Wolters Kluwer |
| Publication Year: |
2023 |
| Collection: |
Oxford University Research Archive (ORA) |
| Description: |
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 ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
https://doi.org/10.1161/CIRCULATIONAHA.120.046464 |
| DOI: |
10.1161/CIRCULATIONAHA.120.046464 |
| Availability: |
https://doi.org/10.1161/CIRCULATIONAHA.120.046464; https://ora.ox.ac.uk/objects/uuid:1fa7a6b4-df0c-43c4-a097-37f2b7caeafd |
| Rights: |
info:eu-repo/semantics/openAccess ; CC Attribution (CC BY) |
| Accession Number: |
edsbas.3231F687 |
| Database: |
BASE |