Sepsis-Induced Lipid Droplet Accumulation Enhances Antibacterial Innate Immunity

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 role of LDs in antibacterial immunity and infection resistance remains less understood. In this study, we investigated triglyceride synthesis and LD accumulation in the context of antibacterial innate immunity during sepsis. Our results show that LD accumulation is part of immunometabolic reprogramming in E. coli-infected macrophages. 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, IFN-{beta}). Notably, DGAT1 inhibition impaired the expression of several interferon-stimulated genes (ISGs), including viperin, iNOS, cathelicidin, and IGTP, in E. coli-infected macrophages. In a sepsis model, DGAT1 inhibition reduced sepsis-induced LD accumulation in peritoneal cells and decreased levels of CCL2, IFN-{beta}, 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 hours post-sepsis. Our results demonstrate that tryglicerides synthesis and LDs are critical regulators of infection resistance, contributing to both bacterial clearance and the coordination of a protective proinflammatory response during sepsis.