BACKGROUND Macrophages are key players in obesity-associated cardiovascular diseases, which are marked by inflammatory and immune alterations. However, the pathophysiological mechanisms underlying macrophage's role in obesity-induced cardiac inflammation are incompletely understood. Our study aimed to identify the key macrophage population involved in obesity-induced cardiac dysfunction and investigate the molecular mechanism that contributes to the inflammatory response. METHODS In this study, we used single-cell RNA-sequencing analysis of Cd45+CD11b+F4/80+ cardiac macrophages to explore the heterogeneity of cardiac macrophages. The CCR2+ (C-C chemokine receptor 2) macrophages were specifically removed by a dual recombinase approach, and the macrophage CCR2 was deleted to investigate their functions. We also performed cleavage under target and tagmentation analysis, chromatin immunoprecipitation-polymerase chain reaction, luciferase assay, and macrophage-specific lentivirus transfection to define the impact of lysozyme C in macrophages on obesity-induced inflammation. RESULTS We find that the Ccr2 cluster undergoes a functional transition from homeostatic maintenance to proinflammation. Our data highlight specific changes in macrophage behavior during cardiac dysfunction under metabolic challenge. Consistently, inducible ablation of CCR2+CX3CR1+ macrophages or selective deletion of macrophage CCR2 prevents obesity-induced cardiac dysfunction. At the mechanistic level, we demonstrate that the obesity-induced functional shift of CCR2-expressing macrophages is mediated by the CCR2/activating transcription factor 3/lysozyme 1/NF-κB (nuclear factor kappa B) signaling. Finally, we uncover a noncanonical role for lysozyme 1 as a transcription activator, binding to the RelA promoter, driving NF-κB signaling, and strongly promoting inflammation and cardiac dysfunction in obesity. CONCLUSIONS Our findings suggest that lysozyme 1 may represent a potential target for the diagnosis of obesity-induced inflammation and the treatment of obesity-induced heart disease.

中文翻译：

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溶菌酶 1 发炎的 CCR2+ 巨噬细胞促进肥胖引起的心脏功能障碍。


背景巨噬细胞是肥胖相关心血管疾病的关键参与者，其特征是炎症和免疫改变。然而，巨噬细胞在肥胖引起的心脏炎症中发挥作用的病理生理机制尚不完全清楚。我们的研究旨在确定参与肥胖引起的心脏功能障碍的关键巨噬细胞群，并研究导致炎症反应的分子机制。方法在本研究中，我们利用Cd45+CD11b+F4/80+心脏巨噬细胞的单细胞RNA测序分析来探讨心脏巨噬细胞的异质性。通过双重组酶方法特异性去除CCR2+（CC趋化因子受体2）巨噬细胞，并删除巨噬细胞CCR2以研究其功能。我们还进行了靶标和标签分析、染色质免疫沉淀-聚合酶链反应、荧光素酶测定和巨噬细胞特异性慢病毒转染下的切割，以确定巨噬细胞中溶菌酶 C 对肥胖诱导的炎症的影响。结果我们发现 Ccr2 簇经历了从稳态维持到促炎症的功能转变。我们的数据强调了代谢挑战下心脏功能障碍期间巨噬细胞行为的特定变化。一致地，CCR2+CX3CR1+巨噬细胞的诱导消融或巨噬细胞CCR2的选择性删除可以预防肥胖引起的心脏功能障碍。在机制水平上，我们证明肥胖诱导的表达 CCR2 的巨噬细胞的功能转变是由 CCR2/激活转录因子 3/溶菌酶 1/NF-κB（核因子 kappa B）信号传导介导的。 最后，我们发现了溶菌酶 1 作为转录激活剂的非典型作用，它与 RelA 启动子结合，驱动 NF-κB 信号传导，并强烈促进肥胖中的炎症和心脏功能障碍。结论 我们的研究结果表明，溶菌酶 1 可能是诊断肥胖引起的炎症和治疗肥胖引起的心脏病的潜在靶点。