ASGR1 induces neutrophil extracellular traps formation to exacerbate sepsis-induced myocardial injury and cardiac dysfunction through SLC7A11 ubiquitination

BACKGROUND: Cardiac dysfunction is a crucial culprit for the high mortality of sepsis in intensive care units. The underlying targets and mechanisms of sepsis-induced myocardial dysfunction (SIMD) in sepsis are awaiting profound exploration. The present study investigates the contribution and mechanism of ASGR1 to the progression of SIMD. Herein, we show that ASGR1 in heart tissue is highly related to SIMD. Anti-Ly6G and GSK484 deplete neutrophils and neutrophil extracellular traps (NETs), alleviating myocardial injury and cardiac dysfunction, and promoting survival of LPS-challenged mice. Neutrophils and NETs are observably declined in ASGR1 knockout mice and conditional knockout neutrophils, respectively. In ASGR1 deficiency mice, LPS challenge results in elevated neutrophils and NETs using FACS and confocal microscopy, respectively, leading to reduced myocardial dysfunction and mortality. ASGR1 promotes neutrophil activation and NET accumulation via SLC7A11-dependent ferroptosis. ASGR1 acts as a bridge to transfer the attached ubiquitin to SLC7A11 and facilitates K48-linked ubiquitination degradation of SLC7A11 by SOCS2. Our findings suggest that ASGR1 is a principal indicator of SIMD by inducing NET formation. In addition, the regulation of NET formation could be a potential treatment for SIMD.