From fat to fire: The lipid–inflammasome connection

Summary Inflammasomes are multiprotein complexes that play a crucial role in regulating immune responses by governing the activation of Caspase‐1, the secretion of pro‐inflammatory cytokines, and the induction of inflammatory cell death, pyroptosis. The inflammasomes are pivotal in effective host defense against a range of pathogens. Yet, overt activation of inflammasome signaling can be detrimental. The most well‐studied NLRP3 inflammasome has the ability to detect a variety of stimuli including pathogen‐associated molecular patterns, environmental irritants, and endogenous stimuli released from dying cells. Additionally, NLRP3 acts as a key sensor of cellular homeostasis and can be activated by disturbances in diverse metabolic pathways. Consequently, NLRP3 is considered a key player linking metabolic dysregulation to numerous inflammatory disorders such as gout, diabetes, and atherosclerosis. Recently, compelling studies have highlighted a connection between lipids and the regulation of NLRP3 inflammasome. Lipids are integral to cellular processes that serve not only in maintaining the structural integrity and subcellular compartmentalization, but also in contributing to physiological equilibrium. Certain lipid species are known to define NLRP3 subcellular localization, therefore directly influencing the site of inflammasome assembly and activation. For instance, phosphatidylinositol 4‐phosphate plays a crucial role in NLRP3 localization to the trans Golgi network. Moreover, new evidence has demonstrated the roles of lipid biosynthesis and trafficking in activation of the NLRP3 inflammasome. This review summarizes and discusses these emerging and varied roles of lipid metabolism in inflammasome activation. A deeper understanding of lipid‐inflammasome interactions may open new avenues for therapeutic interventions to prevent or treat chronic inflammatory and autoimmune conditions.