Inflammasomes: molecular regulation and implications for metabolic and cognitive diseases.
Inflammasomes: molecular regulation and implications for metabolic and cognitive diseases.
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DOI：
10.14348/molcells.2014.0104
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发表时间：
2014-06
影响因子：
3.8
通讯作者：
Ryter SW
中科院分区：
文献类型：
--
作者：
Choi AJ;Ryter SW
炎性小体是调节先天免疫和炎症反应的特殊信号平台。各种NLR家族成员（即，NLRP 1、NLRP 3和IPAF）以及PYHIN家族成员AIM 2可以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），其继而催化选择的促炎细胞因子的成熟，包括白细胞介素（IL）-1β和IL-18。NLRP 3炎性体的激活通常需要两个启动信号。Toll样受体（TLR）和NOD样受体（NLR）激动剂通过NF-κ B依赖性启动信号激活促炎细胞因子基因的转录。暴露于细胞外ATP后，刺激P2 X嘌呤受体-7（P2 X7 R）导致K+外流，这是NLRP 3炎性小体形成所需的第二个信号。NLRP 3活化的替代模型涉及溶酶体去稳定化和吞噬NADPH氧化酶和/或胞浆依赖性活性氧（ROS）产生。在这篇综述中，我们研究了激活NLRP 3炎性体通路的调节机制。此外，我们还讨论了NLRP 3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疗法可能在不久的将来导致可能的临床应用。
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.