Journal of inflammation research · 2026
Remodeling of Cardiac Macrophage Subsets Serves as a Critical Driver of Early Diabetic Myocardial Injury.
СтатьяНазвание и аннотация: Перевод в очереди
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Xu Kun, Zhang Ying-Min, Yang Lan, Zhang Li, Zhang Yun-Wen, Guo Jia-Qi, Cai Jian-Ping
Аннотация
BACKGROUND: Diabetic cardiomyopathy (DCM) is a major complication of diabetes; however, the mechanisms underlying cardiac immune microenvironment dysregulation in early DCM remain to be systematically elucidated.
METHODS: An early-stage DCM mouse model was induced by a high-fat/high-fructose regimen combined with streptozotocin, characterized by molecular pathology (oxidative stress, apoptosis) without overt cardiac dysfunction. Using an integrated approach including single-cell RNA sequencing, flow cytometry, and immunofluorescence, we systematically analyzed and validated the pathological remodeling of the cardiac immune microenvironment at the transcriptional, protein expression, and tissue-in-situ levels.
RESULTS: In early DCM, the cardiac immune microenvironment becomes already dysregulated, with significant increases in monocytes, dendritic cells, basophils, NK cells, and T cells. Macrophages, as the central regulators of cardiac immune homeostasis, undergo profound remodeling during this stage. On the one hand, apoptosis of a subset of resident macrophages leads to a deficiency in endogenous protective mechanisms. On the other hand, macrophage subsets derived from peripheral monocytes expand substantially and differentiate into functionally specialized subpopulations: pro-inflammatory (Ccr2⁺MHCIIhi), pro-fibrotic (Ccr2⁺Spp1⁺), and lipid-reprogrammed (Fabp4⁺) subsets. Further analysis revealed that the Ccr2⁺MHCIIhi macrophage subset may drive a self-amplifying cycle of inflammation by promoting monocyte recruitment. Collectively, these changes establish a self-sustaining pathological immune microenvironment that drives early cardiac injury.
CONCLUSION: Using an early DCM mouse model, this study revealed a profound shift in the cardiac immune microenvironment from homeostasis toward inflammation-fibrosis-lipid reprogramming, with macrophage subset remodeling serving as a central driver of early injury. Targeting the recruitment signals mediated by Ccr2⁺MHCIIhi macrophages or protecting the homeostasis of resident macrophages may offer novel therapeutic strategies for intervening in the progression of diabetic cardiomyopathy.
METHODS: An early-stage DCM mouse model was induced by a high-fat/high-fructose regimen combined with streptozotocin, characterized by molecular pathology (oxidative stress, apoptosis) without overt cardiac dysfunction. Using an integrated approach including single-cell RNA sequencing, flow cytometry, and immunofluorescence, we systematically analyzed and validated the pathological remodeling of the cardiac immune microenvironment at the transcriptional, protein expression, and tissue-in-situ levels.
RESULTS: In early DCM, the cardiac immune microenvironment becomes already dysregulated, with significant increases in monocytes, dendritic cells, basophils, NK cells, and T cells. Macrophages, as the central regulators of cardiac immune homeostasis, undergo profound remodeling during this stage. On the one hand, apoptosis of a subset of resident macrophages leads to a deficiency in endogenous protective mechanisms. On the other hand, macrophage subsets derived from peripheral monocytes expand substantially and differentiate into functionally specialized subpopulations: pro-inflammatory (Ccr2⁺MHCIIhi), pro-fibrotic (Ccr2⁺Spp1⁺), and lipid-reprogrammed (Fabp4⁺) subsets. Further analysis revealed that the Ccr2⁺MHCIIhi macrophage subset may drive a self-amplifying cycle of inflammation by promoting monocyte recruitment. Collectively, these changes establish a self-sustaining pathological immune microenvironment that drives early cardiac injury.
CONCLUSION: Using an early DCM mouse model, this study revealed a profound shift in the cardiac immune microenvironment from homeostasis toward inflammation-fibrosis-lipid reprogramming, with macrophage subset remodeling serving as a central driver of early injury. Targeting the recruitment signals mediated by Ccr2⁺MHCIIhi macrophages or protecting the homeostasis of resident macrophages may offer novel therapeutic strategies for intervening in the progression of diabetic cardiomyopathy.