TREM2hi resident macrophages protect the septic heart by maintaining cardiomyocyte homeostasis

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.

Automated summary

Sepsis-induced cardiomyopathy (SICM) is a common and highly fatal condition characterized by abnormal immune response. This study identifies a unique subpopulation of cardiac-resident macrophages, CD163(+)RETNLA(+) (Mac1), which play a crucial role in SICM and can be targeted for prevention. The study demonstrates that TREM2(hi) Mac1 cells actively scavenge dysfunctional mitochondria and their deficiency leads to impaired self-renewal capability, excessive inflammation, cardiac dysfunction, and reduced survival. Intrapericardial administration of TREM2(hi) Mac1 cells can prevent SICM, suggesting a potential therapeutic strategy.