NLRP3 Inflammasome Activation in Adipose Tissues and Its Implications on Metabolic Diseases

Abstract

Adipose tissue is an active endocrine and immune organ that controls systemic immunometabolism via multiple pathways. Diverse immune cell populations reside in adipose tissue, and their composition and immune responses vary with nutritional and environmental conditions. Adipose tissue dysfunction, characterized by sterile low-grade chronic inflammation and excessive immune cell infiltration, is a hallmark of obesity, as well as an important link to cardiometabolic diseases. Amongst the pro-inflammatory factors secreted by the dysfunctional adipose tissue, interleukin (IL)-1β, induced by the NLR family pyrin domain-containing 3 (NLRP3) inflammasome, not only impairs peripheral insulin sensitivity, but it also interferes with the endocrine and immune functions of adipose tissue in a paracrine manner. Human studies indicated that NLRP3 activity in adipose tissues positively correlates with obesity and its metabolic complications, and treatment with the IL-1β antibody improves glycaemia control in type 2 diabetic patients. In mouse models, genetic or pharmacological inhibition of NLRP3 activation pathways or IL-1β prevents adipose tissue dysfunction, including inflammation, fibrosis, defective lipid handling and adipogenesis, which in turn alleviates obesity and its related metabolic disorders. In this review, we summarize both the negative and positive regulators of NLRP3 inflammasome activation, and its pathophysiological consequences on immunometabolism. We also discuss the potential therapeutic approaches to targeting adipose tissue inflammasome for the treatment of obesity and its related metabolic disorders.

Mitochondria as Key Players in the Pathogenesis and Treatment of Rheumatoid Arthritis

“…Gain-of-function mutations within NLRP3 are associated with the autoinflammatory disease cryopyrin-associated periodic syndrome (CAPS), and aberrant or excessive activation of NLRP3 has been linked to pathogenesis in SLE and various forms of arthritis ( 142 , 144 , 145 ). The NLRP3 inflammasome is also considered to be an important sensor of systemic metabolic disturbance, and is linked to the low-grade inflammation that plays a pathological role in metabolic disorders such as obesity and type 2 diabetes ( 146 ).…”

Regulation of the NLRP3 Inflammasome by Post-Translational Modifications and Small Molecules

“…The NLRP3 inflammasome plays a pivotal role in development and progress of many common inflammatory diseases ( 99 ). The NLRP3 inflammasome has been implicated in the pathogenesis of metabolic disorders such as type 2 diabetes ( 100 ), atherosclerosis ( 101 ), obesity ( 102 ), and gout ( 103 ). In addition, the role of NLRP3 is noted to contribute to the pathology of central nervous system diseases including Alzheimer’s disease ( 104 ) and Parkinson’s disease ( 105 ).…”

Cell lineage-specific methylome and genome alterations in gout

“…VDAC1 also stimulates IL-1β expression in macrophages [ 26 ], and the hypomethylated VDAC1 promoter may promote VDAC1 expression [ 54 , 55 ] and subsequent IL-1β expression in macrophages, thus perpetuating gouty inflammation ( Table 2 , Figure 5 ). CPT1A is also required for IL-1β production in macrophages and may be upregulated in response to 5'UTR hypomethylation [ 27 , 53 ]. The CPT1A hypomethylation observed here therefore likely promotes gout by increasing CPT1A expression and IL-1β production in macrophages ( Table 2 , Figure 5 ).…”