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.

中文翻译：

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高血糖诱导巨噬细胞及其前体的免疫训练并促进动脉粥样硬化

背景：尽管进行降糖治疗，糖尿病患者的心血管风险仍然升高。我们假设高血糖会诱导巨噬细胞训练有素的免疫力，促进持久的致动脉粥样硬化特征。方法：将对照小鼠和糖尿病小鼠的骨髓来源的巨噬细胞在生理葡萄糖 (5 mmol/L) 中生长，并进行 RNA 测序 (n=6) ，转座酶可及染色质测序（n = 6）和染色质免疫沉淀测序（n = 6）测定高血糖诱导的训练免疫力。将患有（n=9）或不患有（n=6）糖尿病的小鼠的骨髓移植到（血糖正常）Ldlr ^{-/ -}小鼠中，以评估其体内功能意义。与对照受试者 (n=16) 相比，在糖尿病患者 (n=8) 的人外周血单核细胞以及通过激光捕获显微切割切除的人动脉粥样硬化斑块巨噬细胞中寻找高血糖诱导的训练有素的免疫力的证据。 结果：在巨噬细胞中，高细胞外葡萄糖通过糖酵解依赖性机制促进促炎基因表达和促动脉粥样硬化功能特征。糖尿病小鼠的骨髓来源的巨噬细胞保留了这些特征，即使在生理葡萄糖中培养时也是如此，这表明高血糖诱导了训练有素的免疫力。将糖尿病小鼠的骨髓移植到（血糖正常）Ldlr ^{-/ -}小鼠中会增加主动脉根动脉粥样硬化，证实了一种与疾病相关且持久的受过训练的先天免疫。对转座酶可及染色质、染色质免疫沉淀以及造血干细胞和骨髓源性巨噬细胞的 RNA 测序分析的综合分析揭示了糖尿病中的促炎启动效应。开放染色质的模式涉及转录因子 Runt 相关转录因子 1 (Runx1)。同样，2 型糖尿病患者的动脉粥样硬化斑块巨噬细胞和外周白细胞的转录组也富含 Runx1 靶标，这与人类疾病中的潜在作用一致。体外对 Runx1 进行药理学抑制可抑制训练表型。 结论：高血糖诱导的训练免疫可能解释了为什么针对升高的血糖不能有效降低糖尿病的大血管风险，并为疾病预防和治疗提供了新的靶点。