ELF4 improves sepsis-induced myocardial injury by regulating STING signaling-mediated T cells differentiation.

Septic cardiomyopathy (SCM) is a common complication caused by sepsis. T cells differentiation is involved in SCM progression. However, the role and underlying mechanisms of T cells-mediated immunity in SCM remain unclear. This study aimed to investigate the role of STING-mediated T cells differentiation in SCM. Cecal ligation and puncture (CLP) surgery was conducted in mice to establish SCM model. The mice were injected intraperitoneally with STING agonist ADU-S100 and C-176 after modeling. Wild type (WT) mice and CD4-STING^-/- mice were employed. Besides, overexpressing vectors of ELF4 (oe-ELF4), short hairpin RNA targeting ELF4 (sh-ELF4) were transfected into 293T cells. STING signaling was found to be activated in sepsis-induced myocardial immune injury in mice. The administration of ADU-S100 exacerbated myocardial injury and inflammation, while C-176 alleviated these effects. Additionally, STING activation influenced T cells differentiation, with an increase in Th1 and Th17 cells and a decrease in Treg cells. Conditional knockout of STING in CD4⁺ T cells reduced Th1 and Th17 populations and improved myocardial function and histology. Furthermore, ELF4 was found to inhibit STING activation, reducing T cells differentiation into pro-inflammatory subsets. Overexpression of ELF4 in CD4⁺ T cells ameliorated myocardial damage and improved cardiac function in CLP mice, suggesting that the ELF4-STING signaling axis plays a protective role in sepsis-induced myocardial injury by regulating T cells differentiation.