In an early diabetic cardiomyopathy mouse model, metabolic stress induced a profound shift in cardiac macrophages, characterized by resident macrophage apoptosis and expansion of pro-inflammatory, pro-fibrotic, and lipid-reprogrammed monocyte-derived subsets.
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⁺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. 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⁺MHCII hi macrophages or protecting the homeostasis of resident macrophages may offer novel therapeutic strategies for intervening in the progression of diabetic cardiomyopathy. The diagram illustrates two conditions within the heart: homeostasis and early-stage diabetic cardiomyopathy. On the left, under homeostasis, various macrophages are labeled, including TLF plus Cxcl13 minus Mac and Ccr2 minus MHCIIhi Mac. These cells are distributed throughout the heart. On the right, early-stage diabetic cardiomyopathy shows changes in cell types and functions. Monocytes are depicted entering the heart, differentiating into various macrophages such as Ccr2 plus MHCIIhi Mac, which are pro-inflammatory, Ccr2 plus Spp1 plus Mac, which are pro-fibrotic and Fabp4 plus Mac, involved in lipid metabolism. Apoptosis is indicated in some cells. Additional immune cells like dendritic cells, natural killer cells, T cells and basophils are shown outside the heart, suggesting their involvement in the condition. The diagram highlights the shift in cellular composition and function between the two states.Diagram comparing heart cell types in homeostasis and early-stage diabetic cardiomyopathy. Keywords: diabetic cardiomyopathy, immune microenvironment, macrophage remodeling, inflammation, lipid metabolic reprogramming
Xu et al. (Mon,) conducted a other in Early-stage diabetic cardiomyopathy (n=41). High-fat/high-fructose diet and streptozotocin vs. Normal diet was evaluated on Proportion of cardiac macrophage subsets. In an early diabetic cardiomyopathy mouse model, metabolic stress induced a profound shift in cardiac macrophages, characterized by resident macrophage apoptosis and expansion of pro-inflammatory, pro-fibrotic, and lipid-reprogrammed monocyte-derived subsets.