Inflammasome activation in obesity-related inflammatory diseases and autoimmunity

Abstract

The inflammasome is a highly regulated protein complex that triggers caspase-1 activation and subsequent secretion of IL-1β and IL-18. Recognition of microbial components and danger signals by NOD-like receptor (NLR) family members in the cytosol promotes inflammasome activation and downstream inflammatory cytokine production. Pathogen recognition by NLRs and downstream release of inflammasome-derived cytokines are important in host defense against numerous infections. Recent studies have also identified a unique role for inflammasome regulation in the induction and pathogenesis of multiple autoimmune and inflammatory disorders. We now know that obesity-related factors and endogenous markers of cellular stress can lead to unchecked activation of the inflammasome and provoke inflammation and subsequent destruction of vital organs. This review will highlight recent findings that link inflammasome signaling to the progression of autoinflammatory and autoimmune diseases. We will focus on the contribution of inflammasome activation to the pathogenesis of autoinflammatory and autoimmune diseases that are of major significance to human health including type 2 diabetes, atherosclerosis, multiple sclerosis, and type 1 diabetes.

Figure 1. Activation of the inflammasome

Pathogen- and danger-associated molecular patterns (PAMPs and DAMPs, respectively) are detected by NLRs in the cytosol. Once activated, the NLR undergoes a conformational change, resulting in the recruitment of ASC and caspase-1 into a protein complex known as the inflammasome. Formation of the inflammasome molecular platform triggers self-cleavage and activation of caspase-1. Active caspase-1 subsequently cleaves the pro-forms of IL-1β and IL-18, which is required for their secretion and biological activity. Inflammasome-derived cytokines (IL-1β and IL-18) are potent mediators of inflammation and immune cell activation. Their immunogenic activity plays a central role in host defense against numerous pathogens. However, unchecked regulation of IL-1β and IL-18 activation in responses to DAMPs (e.g., cellular and metabolic distress, environmental insults, metabolites, etc.) results in chronic inflammation and contributes to the induction and pathogenesis of numerous inflammatory and autoimmune diseases.

Figure 2. Inflammasome activation in atherosclerosis and type 2 diabetes

Obesity-related factors have emerged as important activators of inflammasome-derived cytokines. Cholesterol crystals that develop as a result of high-fat diets and obesity deposit in the arterial walls and incite inflammation via the activation of the NLRP3 inflammasome. Unrestrained production of IL-1β and IL-18 induces the production of additional inflammatory cytokines and provokes the recruitment of immune cells, including macrophages. Inflammasome activation in the cardiovascular system can ultimately result in plaque rupture. Obesity-derived metabolites, including IAAP oligomers and fatty acids (palmitate and ceramide), can induce inflammasome activation, which contributes to the induction and progression of T2D. Furthermore, hyperglycemia and alteration of adipose tissue causes metabolic distress and direct downstream activation of inflammasome signaling. Secretion of IL-1β and IL-18 in the pancreas causes the destruction of insulin producing cells (β-cells) and hyperglycemia. Inflammasome-mediated inflammation in the adipose tissue impairs adipokine production, which is an important regulator of insulin-sensitization. Two commonly prescribed T2D drugs, glyburide and glibenclamide, limit disease partially through their inhibition of inflammasome activation. Weight loss can also limit the secretion of inflammasome-induced cytokines.