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NLRP3 inflammasome in cancer and metabolic diseases

Abstract

The NLRP3 inflammasome is a multimeric cytosolic protein complex that assembles in response to cellular perturbations. This assembly leads to the activation of caspase-1, which promotes maturation and release of the inflammatory cytokines interleukin-1β (IL-1β) and IL-18, as well as inflammatory cell death (pyroptosis). The inflammatory cytokines contribute to the development of systemic low-grade inflammation, and aberrant NLRP3 activation can drive a chronic inflammatory state in the body to modulate the pathogenesis of inflammation-associated diseases. Therefore, targeting NLRP3 or other signaling molecules downstream, such as caspase-1, IL-1β or IL-18, has the potential for great therapeutic benefit. However, NLRP3 inflammasome–mediated inflammatory cytokines play dual roles in mediating human disease. While they are detrimental in the pathogenesis of inflammatory and metabolic diseases, they have a beneficial role in numerous infectious diseases and some cancers. Therefore, fine tuning of NLRP3 inflammasome activity is essential for maintaining proper cellular homeostasis and health. In this Review, we will cover the mechanisms of NLRP3 inflammasome activation and its divergent roles in the pathogenesis of inflammation-associated diseases such as cancer, atherosclerosis, diabetes and obesity, highlighting the therapeutic potential of targeting this pathway.

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Fig. 1: Mechanism of NLRP3 inflammasome activation.
Fig. 2: NLRP3 inflammasome in cancer.
Fig. 3: NLRP3 inflammasome in diabetes and obesity.
Fig. 4: NLRP3 inflammasome in atherosclerosis.

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Acknowledgements

We thank the members of the T.-D.K. laboratory for helpful feedback during the editing of this Review and R. Tweedell for scientific editing and writing support. T.-D.K. is supported by funding from the National Institutes of Health (grants AI101935, AI124346, AR056296 and CA253095) and the American Lebanese Syrian Associated Charities. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Correspondence to Thirumala-Devi Kanneganti.

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Sharma, B.R., Kanneganti, TD. NLRP3 inflammasome in cancer and metabolic diseases. Nat Immunol 22, 550–559 (2021). https://doi.org/10.1038/s41590-021-00886-5

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