Lamp2-Flotillin-2 interaction enhances autophagosome-lysosome fusion to protect the septic heart in response to ILC2
Cardiac dysfunction is a serious complication of sepsis-induced multiorgan failure in intensive care units and is characterized by an uncontrolled immune response to overwhelming infection. Type 2 innate lymphoid cells (ILC2s), as a part of the innate immune system, play a crucial role in the inflammatory process of heterogeneous cardiac disorders. However, the role of ILC2 in regulating sepsis-induced cardiac dysfunction and its underlying mechanism remain unknown. The present study demonstrated that autophagic flux blockage exacerbated inflammatory response and cardiac dysfunction, which was associated with mortality of sepsis. Using a cecal ligation and puncture (CLP) mouse sepsis model, we observed an expansion of ILC2s in the septic heart. Furthermore, IL-4 derived from ILC2 mitigated cardiac inflammatory responses and improved cardiac function during sepsis. Additionally, IL-4 restored the impaired autophagic flux and enhanced lysosomal-associated membrane protein 2 (LAMP2) expression to stabilize lysosomal homeostasis during sepsis. Notably, LAMP2 preferentially bound to Flotillin2 (FLOT2) after IL-4 exposure and the interaction enhanced autophagosome-lysosome fusion in cardiac endothelial cells. Loss of FLOT2 reversed the regulatory effects of LAMP2 on autophagy mediated by IL-4, leading to autophagosome accumulation and suppressed autophagosome clearance. Conclusively, these findings provide novel insights that ILC2 regulates incomplete autophagic flux to protect septic heart and expand our understanding of immunoregulation for sepsis. Overall design: the underlying mechanisms of IL-4 in septic hearts remain unknown. Therefore, heart tissues of control and CLP-induced mice with or without IL-4 treatment were collected for RNA sequencing (RNA-seq) to explore the underlying mechanisms.