Choi Alexander J S, Ryter Stefan W
Center for Sleep Medicine, Department of Pulmonary, Critical Care, and Sleep Medicine, Tufts University School of Medicine.
Mol Cells. 2014 Jun;37(6):441-8. doi: 10.14348/molcells.2014.0104. Epub 2014 May 19.
Inflammasomes are specialized signaling platforms critical for the regulation of innate immune and inflammatory responses. Various NLR family members (i.e., NLRP1, NLRP3, and IPAF) as well as the PYHIN family member AIM2 can form inflammasome complexes. These multi-protein complexes activate inflammatory caspases (i.e., caspase-1) which in turn catalyze the maturation of select pro-inflammatory cytokines, including interleukin (IL)-1β and IL-18. Activation of the NLRP3 inflammasome typically requires two initiating signals. Toll-like receptor (TLR) and NOD-like receptor (NLR) agonists activate the transcription of pro-inflammatory cytokine genes through an NF-κB-dependent priming signal. Following exposure to extracellular ATP, stimulation of the P2X purinoreceptor-7 (P2X7R), which results in K(+) efflux, is required as a second signal for NLRP3 inflammasome formation. Alternative models for NLRP3 activation involve lysosomal destabilization and phagocytic NADPH oxidase and/or mitochondria-dependent reactive oxygen species (ROS) production. In this review we examine regulatory mechanisms that activate the NLRP3 inflammasome pathway. Furthermore, we discuss the potential roles of NLRP3 in metabolic and cognitive diseases, including obesity, type 2 diabetes mellitus, Alzheimer's disease, and major depressive disorder. Novel therapeutics involving inflammasome activation may result in possible clinical applications in the near future.
炎性小体是对先天性免疫和炎症反应调节至关重要的特殊信号平台。各种NLR家族成员（即NLRP1、NLRP3和IPAF）以及PYHIN家族成员AIM2均可形成炎性小体复合物。这些多蛋白复合物激活炎性半胱天冬酶（即半胱天冬酶-1），进而催化特定促炎细胞因子的成熟，包括白细胞介素（IL）-1β和IL-18。NLRP3炎性小体的激活通常需要两个起始信号。Toll样受体（TLR）和NOD样受体（NLR）激动剂通过NF-κB依赖性启动信号激活促炎细胞因子基因的转录。在暴露于细胞外ATP后，刺激P2X嘌呤受体-7（P2X7R）导致K(+)外流，这是NLRP3炎性小体形成的第二个信号。NLRP3激活的其他模型涉及溶酶体去稳定化以及吞噬性NADPH氧化酶和/或线粒体依赖性活性氧（ROS）生成。在本综述中，我们研究了激活NLRP3炎性小体途径的调节机制。此外，我们讨论了NLRP3在代谢和认知疾病中的潜在作用，包括肥胖、2型糖尿病、阿尔茨海默病和重度抑郁症。涉及炎性小体激活的新型疗法可能在不久的将来带来临床应用。
