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J Clin Immunol (2010) 30:628631 DOI 10.1007/s10875-010-9440-3
Molecular Mechanism of NLRP3 Inflammasome Activation
Chengcheng Jin & Richard A. Flavell
Received: 2 June 2010 /Accepted: 6 June 2010 /Published online: 30 June 2010 # Springer Science+Business Media, LLC 2010
Abstract The inflammasome is an intracellular multimolecular complex that controls caspase-1 activity in the innate immune system. NLRP3, a member of the NLR family of cytosolic pattern recognition receptors, along with the adaptor protein ASC, mediates caspase-1 activation via assembly of the inflammasome in response to various pathogen-derived factors as well as danger-associated molecules. The active NLRP3 inflammasome drives innate immune response towards invading pathogens and cellular damage, and regulates adaptive immune response. Here, we review identified agonists of the NLRP3 inflammasome and the molecular mechanism by which they induce NLRP3 inflammasome activation. Three signaling pathways involving potassium efflux, generation of reactive oxygen species, and cathepsin B release are discussed.
Keywords NLRP3 inflammasome . agonist . potassium efflux . reactive oxygen species . cathepsin B
The NOD-like receptors (NLRs) are a large family of intracellular pattern recognition receptors which are comprised of 22 members in human and 34 members in mice [1, 2]. As an important player in the innate immune system,
they are able to recognize a variety of pathogen-associated molecular patterns, as well as host-derived danger signals (danger-associated molecular patterns), and mediate immune response to defend pathogen infection and endogenous damage. Several members of this family such as NLRP1, NLRP3, and NLRC4 have been shown to assemble into large multiprotein complexes named inflammasomes to control caspase-1 activity. Inflammasome-dependent caspase-1 activation may lead to the maturation and secretion of pro-inflammatory cytokines IL-1 and IL-18, and may also drive pyroptosis [3] or mediate unconventional protein secretion [4].
The most thoroughly characterized inflammasome is the NLRP3 inflammasome, which consists of the NLR family member NLRP3, the adaptor protein ASC and the effector protein caspase-1. Thus far, a broad range of exogenous and endogenous stimuli have been demonstrated to activate the NLRP3 inflammasome. These include infecting micro-organisms such as Sendai virus, Influenza virus, adenovirus, the fungi Saccharomyces cerevisiae and Candida albicans, as well as several bacteria like Staphylococcus aureus, Listeria monocytogenes, and Shigella flexneri [58]. In certain cases, the specific microbial components or products that trigger the NLRP3 inflammasome...