Danger signals are a hallmark of many common inflammatory diseases, and these stimuli can function to activate the cytosolic innate immune signalling receptor NLRP3 (NOD-, LRR- and pyrin domain-containing 3). Once activated, NLRP3 nucleates the assembly of an inflammasome, leading to caspase 1-mediated proteolytic activation of the interleukin-1β (IL-1β) family of cytokines, and induces an inflammatory, pyroptotic cell death. Pharmacological inhibition of NLRP3 activation results in potent therapeutic effects in a wide variety of rodent models of inflammatory diseases, effects that are mirrored by genetic ablation of NLRP3. Although these findings highlight the potential of NLRP3 as a drug target, an understanding of NLRP3 structure and activation mechanisms is incomplete, which has hampered the discovery and development of novel therapeutics against this target. Here, we review recent advances in our understanding of NLRP3 activation and regulation, highlight the evolving landscape of NLRP3 modulators and discuss opportunities for pharmacologically targeting NLRP3 with novel small molecules.
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The authors thank L. Franchi for advice during the preparation of this document. E.L. is supported by grants from the Deutsche Forschungsgesellschaft (DFG SFBs 645, 670, 1123; TRRs 83, 57), a grant from the National Institutes of Health (1R01HL112661) and by a European Research Council (ERC) Consolidator grant (InflammAct). E.L. is a member of the excellence cluster ImmunoSensation, which is funded by the DFG.
E.L. is a consultant to IFM Therapeutics. E.J.O., W.R.R., H.M.S. and G.D.G. are employees of IFM Therapeutics.
- Innate immune memory
Epigenetic reprogramming of innate immune cells following an initial encounter with a pathogen, leading to changed chromatin accessibility and altered transcriptional responsiveness in response to subsequent stimuli.
- Antagonistically pleiotropic
A situation in which one gene controls for more than one trait and at least one of these traits is beneficial to the organism's fitness and at least one is detrimental to the organism's fitness.
- ASC speck
Multimeric protein aggregates that result from helical fibril formation of ASC that is initiated by the homo-oligomerization of inflammasome proteins.
A family of cysteine proteases that reside in the lysosomes of cells.
The deliberate, specific degradation of mitochondria by an autophagic mechanism.
An increase in the number of astrocytes that accompanies the death or damage of nearby neuronal cells. The purpose of astrogliosis is likely to limit damage and remove noxious or infectious agents but can lead to scar formation.
A disease in which the lumen of an artery narrows owing to the build-up of a plaque, which, when it ruptures, occludes the vessel and prevents blood flow.
- APP/PS1 mouse line
A double-transgenic mouse line that expresses a chimaeric mouse–human amyloid precursor protein and a mutant human presenilin 1, both of which are expressed in central nervous system neurons.
A type of macrophage, also known as an alternatively activated macrophage, that is considered anti-inflammatory and is important in wound healing and tissue repair.
Substances that enhance the body's immune response to an antigen.
- Delayed-type hypersensitivity
A cell-mediated immune response to an antigen that takes several days to develop.
- Michael acceptors
The accepting molecules in a Michael reaction. The Michael reaction or Michael addition is the nucleophilic addition of a carbanion or another nucleophile to an α,β-unsaturated carbonyl compound.
A service platform that provides over 630 validated in vitro pharmacological assays that cover a broad range of targets, including receptors, ion channels, transporters, enzymes and second messengers. These assays can be used to identify lead compounds, to define mechanism of action and to identify off-target activities.
- Walker A motif
A type of phosphate-binding protein motif.
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Mangan, M., Olhava, E., Roush, W. et al. Targeting the NLRP3 inflammasome in inflammatory diseases. Nat Rev Drug Discov 17, 588–606 (2018). https://doi.org/10.1038/nrd.2018.97
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