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TREM2hi Resident Macrophages Protect the Septic Heart by Maintaining Ccardiomyocytes Homeostasis

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE190856 | GEO | 2022/11/15

REPOSITORIES: GEO

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Project description:Background: Sepsis can lead to multiple organ damage, and the heart is one of the most vulnerable organs. Vagal nerve stimulation can reduce myocardial injury in sepsis and improve survival rate. However, the relative effect of disparate cell populations on sepsis induced myocardial dysfunction and the low-level tragus stimulation on it, remain unclear. Methods: We used the cardiac single-cell transcriptomic strategy to characterize the cardiac cell population and the network of cells that forms the heart. And we selected all cardiac macrophage from CD45+ cells using single-cell mRNA sequencing data. Then we used echocardiography performing, western blot and immunofluorescence and immunohistochemical technology to verify the data of the single-cell mRNA sequencing results. Results: In single-cell mRNA sequencing data, our analysis provides a comprehensive map of the cardiac cellular landscape uncovering multiple cell populations that contribute to sepsis induced myocardial dysfunction under low-level tragus stimulation. Pseudo timing analysis in single-cell sequencing showed that low level vagal nerve stimulation could induce the transformation of cardiac monocytes into M2 macrophages and play an anti-inflammatory role. After low-level tragus stimulation, the expression of α7nAChR in the heart tissue increased significantly. Echocardiography showed that low-level tragus stimulation could improve the cardiac function of septic myocardial injury of the mice. Comparing with the sepsis group, the expression of interleukin-1β in heart tissue of the mice in sepsis with low-level tragus stimulation group is significantly lower. Conclusion: Low-level tragus stimulation can improve sepsis-induced myocardial dysfunction by promoting cardiac monocytes to M2 macrophages. Goal of the study: In the present study, we aimed to screen macrophages, their crosstalk with other cells, and macrophages associated with cardiac injury and further verify their origins and roles in the septic myocardial injury process and low-level tragus stimulation (LL-TS) to treat septic myocardial dysfunction.

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TREM2hi Resident Macrophages Protect the Septic Heart by Maintaining Ccardiomyocytes Homeostasis

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