Nlrp3 Inflammasome Activation in Type 2 Diabetes: Is It Clinically Relevant?

Abstract

Aberrant activation of the innate immune system in metabolic disorders such as type 2 diabetes has been recognized to be an important mechanism of disease pathogenesis (1–3). Emergence of a chronic proinflammatory state driven by the activation of myeloid lineage innate immune cells, such as macrophages and neutrophils, has been directly linked to the emergence of insulin resistance (4,5). Until recently, the identity of specific innate immune pattern recognition receptors or sensors that recognize diverse metabolic “danger signals” to initiate a proinflammatory cascade during obesity and diabetes was unknown. Pioneering studies from Tschopp and colleagues (6) identified that “inflammasomes,” the multiprotein cytosolic molecular platforms in myeloid cells, can sense damage-associated molecular patterns (DAMPs) and control the secretion of proinflammatory cytokines interleukin (IL)-1β and IL-18 in metabolic stress. Structurally, inflammasomes consist of a Nod-like receptor (NLR), the apoptosis-associated speck-like protein containing a CARD (ASC) adaptor protein, and caspase-1 (6). Several NLR molecules including NLRP1, NLRP3, and NLRC4 control caspase-1 activation, which controls the cleavage and secretion of pro–IL-1β and pro–IL-18 into bioactive cytokines (6). Several studies using genetically modified mice that lack inflammasome components Nlrp3, Asc, and caspase-1 provided initial evidence that activation of the Nlrp3 inflammasome is a key mechanism that induces metabolic inflammation and insulin resistance (7–10). Deactivation of the Nlrp3 inflammasome in obese type 2 diabetic patients that lose excess weight through lifestyle intervention is coupled with improved glucose homeostasis, suggesting that inflammasome may be a clinically relevant mechanism that links inflammation with type 2 diabetes (7). However, there is scant clinical evidence that myeloid cells of type 2 diabetic patients have elevated Nlrp3 inflammasome activation, and it is not clear whether …