Department of Anesthesiology and Intensive Care, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Department of Critical Care Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Nat Metab. 2023 Jan;5(1):129-146. doi: 10.1038/s42255-022-00715-5. Epub 2023 Jan 12.
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 CD163RETNLA (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). TREM2 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 Mac1 cells prevents SICM. Our findings suggest that the modulation of TREM2 Mac1 cells could serve as a therapeutic strategy for SICM.
脓毒症相关性心肌病 (SICM) 在脓毒症患者中很常见，死亡率较高，其特征是免疫反应异常。由于细胞异质性，理解免疫细胞亚群在 SICM 中的作用一直具有挑战性。在这里，我们鉴定了一种独特的心脏驻留巨噬细胞亚群，称为 CD163RETNLA (Mac1)，它在脓毒症期间经历自我更新，可以被靶向以预防 SICM。通过在脓毒症小鼠模型中结合单细胞 RNA 测序和命运图谱，我们证明 Mac1 亚群具有丰富的内吞作用的独特转录组特征，并表现出 TREM2（TREM2）的高表达。TREM2 Mac1 细胞可主动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清除缺陷、心脏组织中过度的炎症反应、心脏功能恶化和存活率降低。值得注意的是，心包内给予 TREM2 Mac1 细胞可预防 SICM。我们的研究结果表明，调节 TREM2 Mac1 细胞可能成为 SICM 的一种治疗策略。
