Sirt1 inhibits gouty arthritis via activating PPARγ.

Abstract

To identify the effects of Sirtuin 1 (Sirt1) on gouty arthritis and investigate the underlying mechanisms. A gouty arthritis model was established by intra-articular injection of monosodium urate (MSU, 1mg) crystal solution into the left foot pad of C57BL/6 mice. After pretreating the gouty arthritis mice with intra-articular injection of Sirt1 agonist (Resveratrol, RSV, 20mg/kg) or peroxisome proliferator-activated receptor γ (PPARγ) inhibitor (T0070907, 1mg/kg), the degree of joint inflammation of the gouty arthritis mice was evaluated by clinical integration of joint inflammation and hematoxylin and eosin (H&E) staining. The mRNA expression of Sirt1 and PPARγ were determined by real-time polymerase chain reaction (PCR). The expression profiling of inflammatory cytokines and chemokines in mouse joint tissues were determined by multi-factor assay kits. Peritoneal macrophages were isolated from mice and tested the effects of RSV and/or PPARγ on pro-inflammatory cytokines secretion by PCR. Sirt1 agonist significantly suppressed the onset of gouty arthritis induced by MSU and reduced the infiltration of inflammatory cells in the joints. Sirt1 agonist significantly promoted the expression of PPARγ, while decreased the expression of interleukin (IL)-1β, IL-1α, IL-6, interferon-γ (IFN-γ), monocyte chemotactic protein 1(MCP-1), tumor necrosis factor a (TNF-α), and chemokines (CXCL-1, CXCL-5, CCL-22) induced by MSU in joint tissues. After blocking PPARγ with T0070907 or by siRNA, the anti-inflammatory effect of Sirt1 agonist on gouty arthritis disappeared and the expression of pro-inflammatory molecules were not significantly reduced. Sirt1 may control the acute onset of gouty arthritis in mice by inhibiting the infiltration of inflammatory cells and the secretion of pro-inflammatory molecules through PPARγ. Key Points • Sirt1 and its activator, RSV, attenuate the severity of gouty arthritis in mice. • Sirt1 inhibits the infiltration of inflammatory cells and the secretion of pro-inflammatory molecules in MSU-induced arthritis. • Sirt1 inhibits inflammation partially dependent on PPARγ.