NLRP3 inflammasome: A novel target for T2DM treatment?

Abstract

Inflammation is a double-edged sword for the organism. A proper inflammation response is necessary and beneficial to us in resisting pathogen infection, however, an excessive and continuous inflammation response does harm to the health. In fact, studies over the past decade have strongly linked host inflammatory reaction to the etiology of some chronic diseases. Therefore, “Is inflammation a major cause in all chronic diseases” as one of the 125 scientific questions was proposed by the journal of Science in 2005. Although recent studies have provided direct evidence indicating a key role of chronic inflammation in the initiation and progression of some chronic diseases (such as type 2 diabetes, neurodegenerative diseases, atherosclerosis, gout and cancer), the cellular and molecular mechanisms are not very clear, and the exact therapeutic targets have not been characterized yet. In the recent years, with the in-depth study of the innate immune pattern recognition receptors (PRR) and the mechanism of signal transduction, people found that NLRP3 receptor as well as other PRRs could arouse inflammation reaction and subsequently disease by recognition of the danger signals, which indicated that the PRRs and the related signal pathways may be novel therapeutic targets for the type 2 diabetes and other chronic diseases. Here we summarize the molecular mechanisms of NLRP3 inflammasome activation in response to metabolic danger associated molecular patterns (DAMPs) and discuss the potential therapeutic treatment for type 2 diabetes by targeting to the NLRP3 inflammasome. NLRP3, one of the most-extensively studied NLR sub-family members, has an evolutionarily conserved arrangement of nucleotide binding domain (NBD) for the complex assemble and followed by a leucine rich region (LRR) for the recognition of pattern-associated molecular pattern (PAMP) and damage-associated molecular pattern (DAMP). Two signal pathways are required for the activation of NLRP3 inflammasome. Signal one is provided by the agents of indicated TLRs which aim at inducing nlrp3/IL-1 β transcription and subsequent production of pro-IL-1 β usually provided by glucose, palmitate, uric acid, or LPS. In order to facilitate processing of pro-IL-1 β /18 into their mature forms, signal two is essential to facilitate inflammasome activation and caspase-1-dependent cleavage of pro-IL-1 β /18. In addition, NLRP3-dependent activation of caspase-1 also can be triggered by palmitate, ceramide, glucose, uric acid, reactive oxygen species (ROS), and amyloid. Promotion of this cascade occurs in a variety of tissues, including the pancreas, liver, and adipose tissue and may subsequently contribute to tissue dysfunction and the development of insulin resistance. Inhibition of the IL-1R signaling or IL-1 β production by the NLRP3-dependent activation of caspase-1 may ward off loss of pancreatic β cell function, yet may also prevent the development of insulin resistance in liver, muscle, and adipose tissue. Although clinical evidence is currently lacking, inhibition of the IL-1R signaling or IL-1 β production may avert the development of insulin resistance, which represents an attractive therapeutic target to limit pathological complications associated with obesity, insulin resistance, and type 2 diabetes.