Sepsis-induced cardiomyopathy (SICM) is common in septic patients with a high mortality and is characterized by an abnormal immune response. Owing to cellular heterogeneity, understanding the roles of immune cell subsets in SICM has been challenging. Here we identify a unique subpopulation of cardiac-resident macrophages termed CD163⁺RETNLA⁺ (Mac1), which undergoes self-renewal during sepsis and can be targeted to prevent SICM. By combining single-cell RNA sequencing with fate mapping in a mouse model of sepsis, we demonstrate that the Mac1 subpopulation has distinct transcriptomic signatures enriched in endocytosis and displays high expression of TREM2 (TREM2^hi). TREM2^hi Mac1 cells actively scavenge cardiomyocyte-ejected dysfunctional mitochondria. Trem2 deficiency in macrophages impairs the self-renewal capability of the Mac1 subpopulation and consequently results in defective elimination of damaged mitochondria, excessive inflammatory response in cardiac tissue, exacerbated cardiac dysfunction and decreased survival. Notably, intrapericardial administration of TREM2^hi Mac1 cells prevents SICM. Our findings suggest that the modulation of TREM2^hi Mac1 cells could serve as a therapeutic strategy for SICM.

脓毒症诱发的心肌病 (SICM) 在脓毒症患者中很常见，死亡率很高，其特点是免疫反应异常。由于细胞异质性，了解免疫细胞亚群在 SICM 中的作用一直具有挑战性。在这里，我们确定了一个独特的心脏驻留巨噬细胞亚群，称为 CD163 ⁺ RETNLA ⁺ (Mac1)，它在脓毒症期间进行自我更新，可以作为预防 SICM 的目标。通过将单细胞 RNA 测序与脓毒症小鼠模型中的命运映射相结合，我们证明 Mac1 亚群具有明显的转录组学特征，富含内吞作用并显示 TREM2 (TREM2 hi ) 的高^表达。TREM2^嗨Mac1 细胞积极清除心肌细胞排出的功能失调的线粒体。巨噬细胞中的Trem2缺陷会损害 Mac1 亚群的自我更新能力，从而导致受损线粒体的消除缺陷、心脏组织过度炎症反应、心功能障碍加剧和存活率下降。值得注意的是，TREM2 ^hi Mac1 细胞的心包内给药可预防 SICM。^{我们的研究结果表明，TREM2 hi} Mac1 细胞的调节可以作为 SICM 的治疗策略。