The NLRP3 inflammasome has a prominent role in the pathogenesis of inflammatory arthritis, particularly gout. Several approaches are currently being explored to target the NLRP3 inflammasome as a strategy for the treatment of gout, most of which target the NACHT domain of NLRP3. A new study that aimed to investigate molecules that target the pyrin domain of NLRP3 suggests that β-carotene might have potential as a future therapy for gout.
“Although the antioxidant activity of β-carotene, a plant-derived provitamin A, has been widely reported, our study is the first report to provide the mechanistic detail as to how β-carotene supplementation might prevent NLRP3 inflammasome-related diseases such as gouty arthritis,” states corresponding author Joo Y. Lee.
The researchers began by establishing β-carotene as a promising binding candidate for the pyrin domain of NLRP3. “We ran molecular docking modelling screening with ~62,800 compounds and selected β-carotene as an NLRP3 inflammasome inhibitor, then identified the direct binding mode between β-carotene and the pyrin domain of NLRP3 using surface plasmon resonance analysis and NLRP3 mutation experiments,” says Lee.
In mouse models of gouty arthritis of the knee and foot, administration of oral β-carotene prior to injection with monosodium urate crystals reduced the severity of disease and prevented the production of IL-1β and caspase 1 (products of the NLRP3 inflammasome). Furthermore, the administration of β-carotene to cells from the synovial fluid of patients with gout reduced their secretion of IL-1β in a dose-dependent manner.
“Our findings suggest that pharmacological application of β-carotene might improve inflammatory symptoms related to the NLRP3 inflammasome, such as those experienced by patients with gout,” concludes Lee.
Yang, G. et al. Direct binding to NLRP3 pyrin domain is a novel strategy to prevent NLRP3-driven inflammation and gouty arthritis. Arthritis Rheumatol. https://doi.org/10.1002/ART.41245 (2020)
So, A. K. & Martinon, F. Inflammation in gout: mechanisms and therapeutic targets. Nat. Rev. Rheumatol. 13, 639–647 (2017)
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Clarke, J. β-carotene blocks the inflammasome. Nat Rev Rheumatol 16, 248 (2020). https://doi.org/10.1038/s41584-020-0415-3