Investigating the role of lipid droplets in inflammasome activation

Abstract

Excessive or uncontrolled inflammatory responses drives the progression of numerous prevalent metabolic disorders, including type 2 diabetes, atherosclerosis, and chronic kidney disease. A major contributor to this inflammatory burden is the NLRP3 inflammasome, a key innate immune complex activated by diverse stimuli. Despite growing research in immunometabolism, the precise metabolic pathways that regulate NLRP3 inflammasome activation remain poorly defined. Lipids have emerged as key mediators of inflammasome activation, facilitating inflammasome assembly and activation. When in excess, lipids are directed towards lipid storage organelles known as lipid droplets (LDs). Accumulation of these LDs is a hallmark of numerous immunometabolic disorders, yet whether LDs play a role in inflammatory responses and inflammasome activation remains unexplored. My research establishes that LD accumulation in macrophages potentiates NLRP3 inflammasome activation, enhancing caspase-1 cleavage, GSDMD-mediated pyroptosis, and maturation and release of pro-inflammatory cytokine IL-1β. Furthermore, I reveal that LD accumulation is accompanied by increased interaction between LD and mitochondria, giving rise to a distinct mitochondrial population known is peridroplet mitochondria (PDM). LD accumulation promoted enhanced mitochondrial bioenergetic capacity and ATP- linked respiration which facilitated inflammasome activation. Mechanistically, this was attributed to enhanced PI4P pool at the TGN, facilitating more efficient NLRP3 translocation to dispersed TGN, a key step for NLRP3 inflammasome. Notably, this was dependent on glutaminolysis, revealing a critical role for glutamine metabolism in mediating inflammasome activation. Intriguingly, these mechanistic insights extent to hyperglycaemia-driven NLRP3 inflammasome activation. Identification of this previously unrecognised metabolic-inflammatory axis may offer therapeutic opportunities to resolve dysregulated immune activation in inflammatory and metabolic conditions.