Inflammasomes and obesity

Inflammasomes are a family of protein complexes that recognize diverse microbial and endogenous danger signals to promote innate immune responses, tissue inflammation and injury, or cell death via pyroptosis. Inflammasome activation results in the recruitment and activation of caspase-1, which is required for the production of the proinflammatory cytokines interleukin-1ß (IL-1ß) and IL-18 that can modulate both adaptive and innate immune responses through effects on leukocyte survival, proliferation, differentiation, and migration. Recent studies suggest that inflammasome activity may also play important roles in several nonmicrobial disease states associated with chronic inflammation. For example, NLRP3 inflammasome expression and IL-1ß production are both increased in obesity, and recent work has implicated NLRP3 inflammasome activation in a variety of obesity-linked conditions including gout, type 2 diabetes mellitus, metabolic liver disease, atherosclerosis, Alzheimer's disease, cancer and rheumatoid arthritis. Further, many of the factors associated with these conditions, including elevated plasma glucose, fatty acids, uric acid and cholesterol crystals, and ß-amyloid, have been shown to be elevated during obesity and to stimulate NLRP3 inflammasome expression or activation. Since chronic NLRP3 activation appears to play important roles in several common disease states, better understanding of inflammasome regulation and function may lead to better therapeutic approaches. Several agents that attenuate NLRP3 inflammasome activity or inhibit its primary effector, IL-1ß, are currently under development or in early clinical trials as therapeutics to treat these common disease conditions. This chapter will review new research on inflammasome activation, its role in obesity and other chronic inflammatory states, and the status of approaches to attenuate NLRP3 inflammasome activity.