Remodeling of Cardiac Macrophage Subsets Serves as a Critical Driver of Early Diabetic Myocardial Injury

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.

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.

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⁺MHCII^hi), pro-fibrotic (Ccr2⁺Spp1⁺), and lipid-reprogrammed (Fabp4⁺) subsets. Further analysis revealed that the Ccr2⁺MHCII^hi 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.

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⁺MHCII^hi macrophages or protecting the homeostasis of resident macrophages may offer novel therapeutic strategies for intervening in the progression of diabetic cardiomyopathy.