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 (TREM2hi). TREM2hi 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 TREM2hi Mac1 cells prevents SICM. Our findings suggest that the modulation of TREM2hi Mac1 cells could serve as a therapeutic strategy for SICM.

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Background: The aim of this study was to evaluate the clinical characteristics of 2 rat models of sepsis for improved cecal ligation/puncture (CLP) and feces intraperitoneal-injection (FIP), including systemic inflammation, organ dysfunction, and blood coagulation. Material/Methods: Sixty-two male SD rats were randomly divided into 3 groups: a normal control group (NC, n=6), a CLP group (n=28), and a FIP group (n=28). Ten rats each in the CLP and FIP groups were observed for 72-h mortality rate. The remaining 18 rats in each group were divided into 3 subgroups (n=6) according to their post-operation period (6, 12, and 24 h). Abdominal arterial blood was collected to determine the lactic acid (Lac) concentration, prothrombin time (PT), active partial prothrombin time (APTT), plasmic interleukin-6 (IL-6) level, and cardiac troponin (cTnI) level. The intestines, lung, and heart were collected for pathological examination. Results: The 72-h mortality rates in the CLP and FIP groups were 60% and 100%, respectively. The Lac level in both groups was significantly elevated at 6, 12, and 24 h after modeling. Compared with the NC group, PT in the CLP and FIP groups was prolonged at 12 and 24 h, and APTT was significantly prolonged at 6 h. IL-6 levels in the CLP and FIP groups peaked at 6 h. The cTnI level in the FIP group was significantly higher at 12 h after modeling compared with the NC group. The intestines, lung, and heart were pathologically damaged at 6 h, and this damage worsened over time. Conclusions: Both modeling methods induced sepsis in rats and closely mimicked the clinical conditions, but FIP was easier to establish and was more suitable for standardization.

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