Lawlor Kate E, Vince James E
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, the University of Melbourne, Parkville, Victoria 3050, Australia.
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, the University of Melbourne, Parkville, Victoria 3050, Australia.
Biochim Biophys Acta. 2014 Apr;1840(4):1433-40. doi: 10.1016/j.bbagen.2013.08.014. Epub 2013 Aug 27.
The NLRP3 inflammasome is a sensor of specific pathogen, host and environmental danger molecules. Upon activation NLRP3 recruits caspase-1, which cleaves and thereby activates precursor interleukin-1β (IL-1β) and IL-18 to initiate immune responses. Several recent studies have posited that the mitochondria are a central regulator of NLRP3 function.
Mitochondrial reactive oxygen species (mtROS) production, mitochondrial apoptosis, mitochondrial DNA (mtDNA) release, mitophagy, calcium induced mitochondrial damage and mitochondrial co-ordination of NLRP3 localization have all been implicated in regulating NLRP3 activity. In this article we review the literature both for and against these models of NLRP3 inflammasome activation, and highlight other recent contentious issues concerning NLRP3 functioning.
Although many mechanisms have been proposed for activating NLRP3, no unified model has yet to gain acceptance. Further research is required to clarify how the mitochondria might influence NLRP3 activity.
While the NLRP3 inflammasome is important for host protection against microbial infection, rare genetic mutations in NLRP3 also cause severe auto-inflammatory diseases. More recent research has implicated NLRP3 activity in pathologies such as atherosclerosis, cancer, type 2 diabetes and Alzheimer's disease. Understanding the mechanisms of NLRP3 inflammasome formation and regulation therefore has the potential to uncover new inflammasome and disease specific therapeutic targets. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research.
NLRP3炎性小体是特定病原体、宿主及环境危险分子的感受器。激活后，NLRP3招募半胱天冬酶-1，后者切割并激活白细胞介素-1β（IL-1β）前体和IL-18以启动免疫反应。最近的几项研究认为线粒体是NLRP3功能的核心调节因子。
线粒体活性氧（mtROS）生成、线粒体凋亡、线粒体DNA（mtDNA）释放、线粒体自噬、钙诱导的线粒体损伤以及NLRP3定位的线粒体协调均与NLRP3活性调节有关。在本文中，我们综述了支持和反对这些NLRP3炎性小体激活模型的文献，并强调了其他有关NLRP3功能的近期争议问题。
尽管已提出多种激活NLRP3的机制，但尚未有统一模型被广泛接受。需要进一步研究以阐明线粒体如何影响NLRP3活性。
虽然NLRP3炎性小体对宿主抵御微生物感染很重要，但NLRP3中的罕见基因突变也会导致严重的自身炎症性疾病。最近的研究表明NLRP3活性与动脉粥样硬化、癌症、2型糖尿病和阿尔茨海默病等病理状况有关。因此，了解NLRP3炎性小体形成和调节的机制有可能揭示新的炎性小体和疾病特异性治疗靶点。本文是名为《线粒体研究前沿》特刊的一部分。
