Sepsis-induced lipid droplet accumulation enhances antibacterial innate immunity through mechanisms dependent on DGAT-1 and interferon-beta.

Abstract

Lipid droplets (LDs) are lipid-rich organelles recognized as central players in lipid homeostasis, signaling, and inflammation. While their functions in inflammation are well-documented, the mechanisms of LDs in antibacterial immunity and infection resistance remain less understood. Our results show that E. coli-infection trigger immunometabolic reprogramming and LD accumulation in macrophages. Moreover, purified LDs from LPS-stimulated and E. coli-infected macrophages exhibited direct E. coli anti-bacterial activity. Pharmacological inhibition or genetic knockdown of DGAT1, a key enzyme in triglyceride synthesis, reduced LD formation, bacterial clearance, and pro-inflammatory responses (nitric oxide, PGE₂, CCL2, IL-6). Notably, DGAT1 inhibition impaired the expression of IFN-β and several interferon-stimulated genes (ISGs), including viperin, iNOS, cathelicidin and IGTP, in E. coli-infected macrophages. In a cecal-ligation and puncture model of sepsis in C57BL/6 mice, DGAT1 inhibition reduced sepsis-induced LD accumulation in peritoneal cells and decreased levels of IFN-β, CCL2, nitric oxide, and lipid mediators (PGE₂, LTB₄, and RvD1). Furthermore, DGAT1 inhibition accelerated sepsis-related mortality, coinciding with elevated bacterial loads in the peritoneum and bloodstream at 6- and 24-h post-sepsis. Our results demonstrate that LDs are critical regulators of innate immunity infection resistance, contributing to both bacterial clearance and the coordination of a protective proinflammatory response during sepsis through mechanisms dependent on DGAT-1 and Type I IFN.