Targeting the NLRP3 inflammasome in chronic inflammatory diseases: current perspectives

Ema Ozaki, Matthew Campbell, Sarah L Doyle, Ema Ozaki, Matthew Campbell, Sarah L Doyle

Abstract

The inflammasome is a molecular platform formed by activation of an innate immune pattern recognition receptor seed, such as NLRP3. Once activated, NLRP3 recruits the adapter ASC (apoptosis-related speck-like protein containing a caspase recruitment domain), which in turn recruits procaspase-1. Procaspase-1 autocatalyzes its cleavage and activation, resulting in maturation of the precursor forms of interleukin (IL)-1β and IL-18 into active proinflammatory cytokines and initiation of pyroptotic cell death. The NLRP3 inflammasome has been implicated in the pathogenesis of a wide variety of diseases, including genetically inherited autoinflammatory conditions as well as chronic diseases in which NLRP3 is abnormally activated. The NLRP3 inflammasome has been linked to diseases such as Alzheimer's disease, atherosclerosis, metabolic syndrome, and age-related macular degeneration. In this review, we describe the NLRP3 inflammasome complex and its activation in disease, and detail the current therapies that modulate either the NLRP3 inflammasome complex itself or the two cytokines it is responsible for activating, ie, IL-1β and IL-18.

Keywords: NLRP3; caspase-1; inflammasome; interleukin-1; interleukin-18; therapeutics.

Figures

Figure 1
Figure 1
NLRP3 inflammasome activation. Pathogenic PAMPs from virus or bacteria, or sterile DAMPs “prime” the inflammasome by activating a TLR inducing NFκB activation and the expression of NLRP3 and pro-IL-1β (signal 1). NLRP3 oligomerizes and recruits ASC and procaspase-1 in response to an activation signal (signal 2). NLRP3 can be activated in response to potassium ion efflux through the ATP-gated P2X7 channel, in response to reactive oxygen species released from damaged mitochondria, or in response to cathepsin B release from damaged lysosomes. Once activated the NLRP3 inflammasome causes the activation of caspase-1 which cleaves the precursor proforms of IL-1β and IL-18 into their mature forms. Abbreviations: ASC, apoptosis-related speck-like protein containing a caspase recruitment domain; ATP, adenosine triphosphate; CARD, caspase recruitment domain; DAMPS, danger or damage associated molecular patterns; IL, interleukin; LRR, leucine-rich repeat; NACHT, central nucleotide-binding and oligomerization; NF-κB, nuclear factor kappa B; P2X7, P2X purinergic receptor 7; PAMPS, pathogen associated molecular patterns; PYD, pyrin domain; ROS, reactive oxygen species; TLR, Toll-like receptor.
Figure 2
Figure 2
Small-molecule blockade of the NLRP3 inflammasome. Cartoon depicting the mode of action of the various small molecule inhibitors described in detail in the text. Abbreviations: ASC, apoptosis-related speck-like protein containing a caspase recruitment domain; ATP, adenosine triphosphate; CARD, caspase recruitment domain; Cys-LT, cysteinyl leukotriene; IKKβ, inhibitor of κB kinase β; IL, interleukin; NF-κB, nuclear factor kappa B; P2X7, P2X purinergic receptor 7; PYD, pyrin domain; TLR, Toll-like receptor.

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Source: PubMed

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