Resveratrol reduces the activation of NLRP3 inflammasomes in rheumatoid arthritis through SIRT1 and ITGB α5β1, especially in patients with high expression of ACPA

Abstract

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease with synovitis as the main pathological change. Previous research has demonstrated that the NLRP3 inflammasome is hyperactivated in RA patients, with its potential mechanism possibly linked to anti-citrullinated protein antibodies (ACPA). However, there are no RA treatment drugs specifically targeting NLRP3 inflammasome in clinical practice currently.

Purpose: Resveratrol (Res) is believed to have pharmacological effects of antioxidant and anti-inflammatory reactions, is a promising natural treatment for RA. This study seeks to explore whether Res exerts its therapeutic effect in RA by inhibiting NLRP3 inflammasome activation.

Methods: In vivo, the influence of Res on the inflammatory responses was observed in both Collagen-Induced Arthritis (CIA) and Citrullinated Collagen-Induced Arthritis (Cit-CIA) models, with a special focus on its impact on the NLRP3 inflammasome activation. In vitro, THP-1 macrophages were stimulated with lipopolysaccharide (LPS) plus ATP or purified ACPA from RA patient serum. The expression and localization of NLRP3 inflammasome-related molecules were assessed using ELISA, immunoblotting, and immunofluorescence. Additionally, molecular docking techniques were employed to predict and analyze the interactions among these molecules following the intervention.

Results: Res could alleviate the inflammatory response and synovial pathological changes in both CIA and Cit-CIA mice while significantly inhibiting NLRP3 inflammasome activation in synovial macrophages. Mechanistically, Res could inhibit the acetylation of NLRP3 via SIRT1, resulting in decreased secretion of caspase-1 p20 and IL-1β p17, which in turn suppresses the activation of the LPS-induced NLRP3 inflammasome. Furthermore, Res could also compete with ACPA for binding to integrin α5β1 (ITGB α5β1), thereby reducing Pannexin channel activity and subsequently decreasing ATP release, which in turn inhibits the activation of ACPA-induced NLRP3 inflammasome.

Conclusion: Res significantly ameliorates arthritis in CIA and Cit-CIA models, and its potential mechanism may be to inhibit NLRP3 inflammasome activation by activating SIRT1 or binding to ITGB α5β1.

Keywords: ACPA; Inflammasome; Inflammation; NLRP3; Resveratrol; Rheumatoid arthritis.