Lipids, inflammasomes, metabolism, and disease

Abstract

Inflammasomes are multi‐protein complexes that regulate the cleavage of cysteine protease caspase‐1, secretion of inflammatory cytokines, and induction of inflammatory cell death, pyroptosis. Several members of the nod‐like receptor family assemble inflammasome in response to specific ligands. An exception to this is the NLRP3 inflammasome which is activated by structurally diverse entities. Recent studies have suggested that NLRP3 might be a sensor of cellular homeostasis, and any perturbation in distinct metabolic pathways results in the activation of this inflammasome. Lipid metabolism is exceedingly important in maintaining cellular homeostasis, and it is recognized that cells and tissues undergo extensive lipid remodeling during activation and disease. Some lipids are involved in instigating chronic inflammatory diseases, and new studies have highlighted critical upstream roles for lipids, particularly cholesterol, in regulating inflammasome activation implying key functions for inflammasomes in diseases with defective lipid metabolism. The focus of this review is to highlight how lipids regulate inflammasome activation and how this leads to the progression of inflammatory diseases. The key roles of cholesterol metabolism in the activation of inflammasomes have been comprehensively discussed. Besides, the roles of oxysterols, fatty acids, phospholipids, and lipid second messengers are also summarized in the context of inflammasomes. The overriding theme is that lipid metabolism has numerous but complex functions in inflammasome activation. A detailed understanding of this area will help us develop therapeutic interventions for diseases where dysregulated lipid metabolism is the underlying cause.

An update on the regulatory mechanisms of NLRP3 inflammasome activation

“…90 Indeed, several lipids, including PIP4, contribute to NLRP3 aggregation and activation of the inflammasome complex. 89,179 These data suggest that metabolic enzymes and metabolite changes directly activate the NLRP3 inflammasome complex. It is likely that data on the detailed molecular mechanisms underlying the regulation of immunometabolism will continue to accumulate in the context of inflammasome activation.…”

“…As danger signals, cholesterol crystals trigger NLRP3 inflammasome activation, and dysregulated lipid metabolism plays a critical role in inflammasome-related diseases. 179 The cholesterol trafficking pathway, the lysosomal efflux of cholesterol through Niemann-Pick C1 (NPC1), is tightly associated with immune responses, particularly NLRP3 inflammasome activation. 180 In addition, the interaction of the cholesterol homeostatic regulator SCAP-SREBP2 with NLRP3 to form a complex that is translocated to the Golgi apparatus leads to the activation of the NLRP3 inflammasome in macrophages.…”

Plants as Sources of Anti-Inflammatory Agents

“…Polyphenolic compounds have drawn significant attention due to their modulation effects on inflammasomes [ 43 ]. These multi-protein complexes are associated with the initiation and progression of metabolic disorders and chronic diseases, such as cancer and neurodegenerative diseases [ 44 ].…”

Intracellular innate immune receptors: Life inside the cell

“…46 Anand discusses the role of inflammasome sensors, particularly NLRP3 and AIM2, in detecting perturbations in metabolic pathways, focusing on how lipids can be involved in inflammasome regulation and contribute to diseases. 47 Dysregulated cholesterol metabolism can activate the NLRP3 and AIM2 inflammasomes, and NLRP3 can sense a variety of metabolic DAMPs, including cholesterol crystals and oxidized mtDNA. 47 The functions of lipid metabolism are diverse and complex, and understanding these functions has significant implications for diseases that are driven by dysregulated metabolism, such as obesity, atherosclerosis, and diabetes.…”

“…47 Dysregulated cholesterol metabolism can activate the NLRP3 and AIM2 inflammasomes, and NLRP3 can sense a variety of metabolic DAMPs, including cholesterol crystals and oxidized mtDNA. 47 The functions of lipid metabolism are diverse and complex, and understanding these functions has significant implications for diseases that are driven by dysregulated metabolism, such as obesity, atherosclerosis, and diabetes.…”