Direct binding to NLRP3 pyrin domain is a novel strategy to prevent NLRP3-driven inflammation and gouty arthritis

Arthritis & Rheumatology
Gabsik YangJoo Young Lee

Abstract

The NLR family pyrin domain-containing 3 (NLRP3) inflammasome is closely linked to the pathophysiology of a wide range of inflammatory diseases. We aimed to identify small molecules that directly bind to NLRP3 to develop pharmacological interventions for NLRP3-related diseases. A structure-based virtual screening analysis was performed with approximately 62,800 compounds to select efficient NLRP3 inhibitors. The production of caspase-1(p10) and IL-1β was measured by immunoblotting and ELISA to examine NLRP3 inflammasome activation. Two gouty arthritis models and an air pouch inflammation model induced by MSU crystal injection were used for in vivo experiments. Primary synovial fluid cells from gout patients were used to determine human relevance. β-Carotene (provitamin A) suppressed the NLRP3 inflammasome activation induced by various activators including MSU crystals, in mouse bone marrow-derived primary macrophages (p<0.05). Surface plasmon resonance analysis demonstrated the direct binding of β-carotene to the pyrin domain (PYD) of NLRP3 (KD =3.41E-06). Molecular modeling and mutation assays revealed the interaction mode between β-carotene and the NLRP3 PYD. Inflammatory symptoms induced by MSU crystals were attenuated by or...Continue Reading

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Citations

Apr 2, 2020·Nature Reviews. Rheumatology·Joanna Clarke
Jun 21, 2020·International Journal of Molecular Sciences·Giovanni ZitoChiara Cipollina
Dec 2, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Lina Y El-SharkawySally Freeman
Feb 4, 2021·Archives of Pharmacal Research·Jin Kyung SeokJoo Young Lee
Dec 5, 2020·Journal of Cell Science·Alexander N R WeberAna Tapia-Abellán
Mar 7, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Nuri ChoiJoo Young Lee
Feb 20, 2021·Frontiers in Immunology·Jin Kyung SeokJoo Young Lee
Apr 15, 2021·Cellular & Molecular Immunology·Seungwha PaikEun-Kyeong Jo
May 1, 2021·Journal of Clinical Medicine·Paola GalozziPaolo Sfriso
Aug 5, 2021·Signal Transduction and Targeted Therapy·Danyang Li, Minghua Wu
Oct 30, 2021·Autoimmunity·Ruixue KongDashan Wang

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