Sirt1 inhibits gouty arthritis via activating PPARγ
Sirt1 inhibits gouty arthritis via activating PPARγ
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Sirt1 通过激活 PPARγ 抑制痛风性关节炎
DOI：
10.1007/s10067-019-04697-w
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发表时间：
2019-11-01
影响因子：
3.4
通讯作者：
Zou, Hejian
中科院分区：
文献类型：
--
作者：
Wang, Juan;Chen, Guangliang;Zou, Hejian
目的观察Sirtuin 1（Sirt 1）对C57 BL/6小鼠痛风性关节炎（gouty arthritis，痛风性关节炎）的治疗作用，并探讨其作用机制。关节腔内注射Sirt 1激动剂（白藜芦醇，RSV，20 mg/kg）或过氧化物酶体增殖物激活受体γ（过氧化物酶体增殖物激活受体γ，PPARγ）抑制剂（T0070907，1 mg/kg）对痛风性关节炎小鼠进行预处理后，通过关节炎临床积分和苏木精-伊红（H&E）染色评价痛风性关节炎小鼠的关节炎症程度。采用实时荧光定量PCR（real-time polymerase chain reaction，PCR）检测Sirt 1和PPARγ mRNA的表达。采用多因子分析试剂盒检测小鼠关节组织中炎性细胞因子和趋化因子的表达谱。结果Sirt 1激动剂能显著抑制MSU诱导的小鼠痛风性关节炎的发病，减少关节炎细胞浸润。Sirt 1激动剂可显著促进MSU诱导的关节组织中PPARγ的表达，降低MSU诱导的关节组织中白细胞介素（IL）-1β、IL-1α、IL-6、干扰素-γ（IFN-γ）、单核细胞趋化蛋白1（MCP-1）、肿瘤坏死因子α（TNF-α）和趋化因子（CXCL-1、CXCL-5、CCL-22）的表达。结论Sirt 1可能通过抑制炎性细胞浸润和促炎分子的分泌，抑制小鼠痛风性关节炎的急性发作。关键点·Sirt 1及其激活剂RSV，减轻小鼠痛风性关节炎的严重程度。Sirt 1抑制MSU诱导的关节炎中炎症细胞的浸润和促炎分子的分泌。Sirt 1部分依赖于PPARγ抑制炎症。
ObjectiveTo identify the effects of Sirtuin 1 (Sirt1) on gouty arthritis and investigate the underlying mechanisms.MethodsA gouty arthritis model was established by intra-articular injection of monosodium urate (MSU, 1 mg) 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, 20 mg/kg) or peroxisome proliferator-activated receptor γ (PPARγ) inhibitor (T0070907, 1 mg/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.ResultsSirt1 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.ConclusionsSirt1 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.