NLRP3炎症小体:2型糖尿病治疗的新靶点?

NLRP3 inflammasome: A novel target for T2DM treatment?

炎症之于机体是一把双刃剑,适度的炎症反应利于机体对抗外界病原微生物的感染,而失调的炎症反应又会使这把利剑挥向机体自身,过度放大或持续存在的炎症反应是导致机体组织损伤和器质性病变的主要原因.事实上,一直以来炎症就被认为与许多慢性疾病的发生发展有着千丝万缕的联系.鉴于此,Science于2005年提出的125个科学问题中就包括"炎症是否是所有慢性疾病发生的重要原因?".尽管在2型糖尿病、神经退行性疾病、动脉粥样硬化、痛风及肿瘤等多种严重危害人类健康的重大疾病中都检测到有慢性炎症参与的证据,但是长期以来慢性炎症在这些疾病当中发生的细胞和分子机制并不清楚,相关抗炎干预靶点也并未得到确切鉴定.近年,随着对固有免疫模式识别受体和信号转导机制的深入研究,人们发现,包括NLRP3在内的一些固有免疫模式识别受体通过识别上述慢性疾病当中的危险信号,从而启动炎症反应和疾病的发生,提示NLRP3等固有免疫模式识别受体及其信号通路可能成为包括2型糖尿病在内的相关炎性疾病治疗的新靶点.本文将着重介绍近年有关NLRP3炎症小体活化与T2DM的关系,以及靶向NLRP3炎症小体的T2DM治疗研究方面的进展.

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？ transcription and subsequent production of pro-IL-1？ usually provided by glucose, palmitate, uric acid, or LPS. In order to facilitate processing of pro-IL-1？/18 into their mature forms, signal two is essential to facilitate inflammasome activation and caspase-1-dependent cleavage of pro-IL-1？/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？ production by the NLRP3-dependent activation of caspase-1 may ward off loss of pancreatic ？ 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？ 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.