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The NLRP3 inflammasome: molecular activation and regulation to therapeutics

Abstract

NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) is an intracellular sensor that detects a broad range of microbial motifs, endogenous danger signals and environmental irritants, resulting in the formation and activation of the NLRP3 inflammasome. Assembly of the NLRP3 inflammasome leads to caspase 1-dependent release of the pro-inflammatory cytokines IL-1β and IL-18, as well as to gasdermin D-mediated pyroptotic cell death. Recent studies have revealed new regulators of the NLRP3 inflammasome, including new interacting or regulatory proteins, metabolic pathways and a regulatory mitochondrial hub. In this Review, we present the molecular, cell biological and biochemical bases of NLRP3 activation and regulation and describe how this mechanistic understanding is leading to potential therapeutics that target the NLRP3 inflammasome.

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Fig. 1: NLRP3 inflammasome priming and activation.
Fig. 2: Post-transcriptional modifications of NLRP3.

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Acknowledgements

This Review was supported by the National Center for Advancing Translational Sciences, US National Institutes of Health (NIH), through grant KL2TR002490 awarded to K.V.S. and by the NIH through grants AI029564, CA156330, DK094779, AI109965 and AI067798 awarded to J.P.-Y.T. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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Glossary

Leucine-rich repeat domain

(LRR domain). In Toll-like receptors (TLRs), the LRR domain mediates the detection of microbial components; it may serve a similar role in certain NLRs (NACHT–LRR proteins). The LRR domain of NLRs and TLRs is structurally similar. It consists of leucine-rich amino acid strands forming a peptide loop. The loops occur as tandem repeats that together form a coil or solenoid and contain constant sequences, as well as unique insertions or variable residues for each ligand.

AIM2

A sensor that combines with the adaptor protein ASC and the protease caspase 1 to form the AIM2 inflammasome. It senses cytosolic double-stranded DNA from bacteria or viruses or from mislocalized self-DNA and contributes to infection defence.

P2X purinoceptor 7

(P2X7). An ATP-gated cation channel that is expressed by haematopoietic cells and participates in cell proliferation and apoptosis. It belongs to the family of purinoceptors for ATP and is responsible for the ATP-dependent activation of NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3).

Caecal ligation and puncture

An experimental model of peritonitis in rodents, in which the caecum is ligated and then punctured, thereby forming a small hole. This leads to leakage of intestinal bacteria into the peritoneal cavity and subsequent peritoneal infection.

Mitophagy

The selective removal of mitochondria by macroautophagy under conditions of nutrient starvation or mitochondrial stress.

Oxidative stress

Cells continuously produce reactive oxygen species (ROS) such as hydrogen peroxide or superoxide anions. Under physiological conditions, mitochondria are the main source, and cellular antioxidants ensure that the redox equilibrium is maintained. During inflammatory responses (and in cancer), excessive production of ROS leads to a metabolic condition known as oxidative stress, which can lead to apoptosis and necrosis.

Autophagy

A cytoplasmic bulk degradation system in which cytoplasmic cargo is targeted and is typically sequestered in double-membrane vesicles, leading to subsequent fusion with the lysosome. This process is essential for the response to starvation because it facilitates the recycling of cellular components. In addition, autophagy can be targeted to intracellular bacteria to restrict their growth.

Urate crystal model

A mouse model of crystal-induced peritonitis that activates the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome.

Pyroptosis

A lytic, inflammatory form of programmed cell death that is triggered by cleavage of gasdermin D by the inflammatory caspase 1, 4, 5 or 11. It is characterized by cytoplasmic swelling, early plasma membrane rupture and nuclear condensation. The cytoplasmic content is released into the extracellular space, and this is thought to augment inflammatory and repair responses.

Neutrophil extracellular traps

(NETs). Fibrous networks that are released into the extracellular environment by neutrophils. They are composed mainly of DNA but also contain proteins from neutrophil granules. NETs act as a mesh that traps microorganisms and exposes them to neutrophil-derived effector molecules.

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Swanson, K.V., Deng, M. & Ting, J.PY. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol 19, 477–489 (2019). https://doi.org/10.1038/s41577-019-0165-0

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