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

  • Circulation. 2021 Sep 21;144(12):961-982. doi: 10.1161/CIRCULATIONAHA.120.046464.
Laurienne Edgar  #  1 ,  Naveed Akbar  #  1 ,  Adam T Braithwaite  1 ,  Thomas Krausgruber  2 ,  Héctor Gallart-Ayala  3  4 ,  Jade Bailey  1 ,  Alastair L Corbin  5 ,  Tariq E Khoyratty  5 ,  Joshua T Chai  1 ,  Mohammad Alkhalil  1 ,  André F Rendeiro  2 ,  Klemen Ziberna  1 ,  Ritu Arya  1 ,  Thomas J Cahill  1 ,  Christoph Bock  2  6 ,  Jurga Laurencikiene  7 ,  Mark J Crabtree  1 ,  Madeleine E Lemieux  8 ,  Niels P Riksen  9 ,  Mihai G Netea  9  10 ,  Craig E Wheelock  3  4 ,  Keith M Channon  1 ,  Mikael Rydén  7 ,  Irina A Udalova  5 ,  Ricardo Carnicer  1 ,  Robin P Choudhury  1
Affiliations
  • 1. 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.).
  • 2. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria (T.K., A.F.R., C.B.).
  • 3. Division of Physiological Chemistry II, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden (H.G.-A., C.E.W.).
  • 4. Department of Respiratory Medicine and Allergy (H.G.-A., C.E.W.), Karolinska University Hospital, Stockholm, Sweden.
  • 5. The Kennedy Institute of Rheumatology, University of Oxford, UK (A.L.C., T.E.K., I.A.U.).
  • 6. Institute of Artificial Intelligence and Decision Support, Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Austria (C.B.).
  • 7. Department of Medicine (H7) (J.L., M.R.), Karolinska University Hospital, Stockholm, Sweden.
  • 8. Bioinfo, Plantagenet, ON, Canada (M.E.L.).
  • 9. Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands (N.P.R.., M.G.N.).
  • 10. Department for Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Germany (M.G.N.).
  • # Contributed equally.
PMID: 34255973 DOI: 10.1161/CIRCULATIONAHA.120.046464
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.

Keywords
diabetes mellitus; epigenetics; glucose; inflammation; macrophages.