TREM2hi Resident Macrophages Protect the Septic Heart by Maintaining Ccardiomyocytes Homeostasis

Sepsis-induced cardiomyopathy (SICM) is common in septic patients with a high mortality and displays an abnormal immune response. Owing to cellular heterogeneity, understanding the roles of immune cell subsets in SICM has been challenging. By combining scRNA-seq with fate-mapping, we identified a unique CD163+RETNLA+ subpopulation (Mac1) of cardiac resident macrophages, which underwent self-renewal during sepsis. The restoration of Mac1 numbers was associated with the improvement of cardiac function. The Mac1 subpopulation had distinct transcriptomic signatures enriched in endocytosis and showed high expression of TREM2 (TREM2hi). In addition, we observed that TREM2hi Mac1 cells actively scavenged cardiomyocyte-ejected dysfunctional mitochondria. Trem2 deficiency in macrophages impaired self-renewal capability of the Mac1 subpopulation and consequently resulted in defective elimination of damaged mitochondria, excessive inflammatory response in cardiac tissue, exacerbated cardiac dysfunction and decreased survival. Intrapericardial administration of TREM2hi Mac1 cells prevented SICM. Our findings suggest that the modulation of TREM2hi Mac1 cells could be a potential therapeutic strategy for SICM. Overall design: Single-cell transcriptomic data are presented from 10 samples. Each sample contains a mixture of cardiac cells from 3 or 4 mice. 4 samples were obtained from WT mice at steady state and 3,7,21 days after CLP. The other 6 samples were from Trem2-/- mice and WT littermate controls at steady state and 3,7 days after CLP, respectively.