Direct Binding to NLRP3 Pyrin Domain as a Novel Strategy to Prevent NLRP3‐Driven Inflammation and Gouty Arthritis

炎症体 痛风 吡喃结构域 炎症 关节炎 炎性关节炎 医学 免疫学 内科学
作者
Gabsik Yang,Hye E. Lee,Su‐Jin Moon,Kyung Mi Ko,Jung Hee Koh,Jin Kyung Seok,Jun‐Ki Min,Tae‐Hwe Heo,Han Chang Kang,Yong‐Yeon Cho,Hye S. Lee,Katherine A. Fitzgerald,Joo Young Lee
出处
期刊:Arthritis & rheumatology [Wiley]
卷期号:72 (7): 1192-1202 被引量:70
标识
DOI:10.1002/art.41245
摘要

Objective The NLRP 3 inflammasome is closely linked to the pathophysiology of a wide range of inflammatory diseases. This study was undertaken to identify small molecules that directly bind to NLRP 3 in order to develop pharmacologic interventions for NLRP 3‐related diseases. Methods A structure‐based virtual screening analysis was performed with ~62,800 compounds to select efficient NLRP 3 inhibitors. The production of caspase 1‐p10 and interleukin‐1β ( IL ‐1β) was measured by immunoblotting and enzyme‐linked immunosorbent assay to examine NLRP 3 inflammasome activation. Two gouty arthritis models and an air pouch inflammation model induced by monosodium urate monohydrate ( MSU ) crystal injection were used for in vivo experiments. Primary synovial fluid cells from gout patients were used to determine the relevance of NLRP 3 inflammasome inhibition in human gout. Results Beta‐carotene (provitamin A) suppressed the NLRP 3 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 NLRP 3 ( K D = 3.41 × 10 −6 ). Molecular modeling and mutation assays revealed the interaction mode between β‐carotene and the NLRP 3 PYD . Inflammatory symptoms induced by MSU crystals were attenuated by oral administration of β‐carotene in gouty arthritis mouse models ( P < 0.05), correlating with its suppressive effects on the NLRP 3 inflammasome in inflamed tissues. Furthermore, β‐carotene reduced IL ‐1β secretion from human synovial fluid cells isolated from gout patients ( P < 0.05), showing its inhibitory efficacy in human gout. Conclusion Our results present β‐carotene as a selective and direct inhibitor of NLRP 3, and the binding of β‐carotene to NLRP 3 PYD as a novel pharmacologic strategy to combat NLRP 3 inflammasome–driven diseases, including gouty arthritis.
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