Department of Medicine, University of Colorado Denver, Aurora, CO, USA.
Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
Arthritis Res Ther. 2018 Aug 3;20(1):169. doi: 10.1186/s13075-018-1664-2.
Activation of the NLRP3 inflammasome in gout amplifies the inflammatory response and mediates further damage. In the current study, we assessed the therapeutic effect of OLT1177, an orally active NLRP3 inflammasome inhibitor that is safe in humans, in murine acute arthritis models.
Zymosan or monosodium urate (MSU) crystals were injected intra-articularly (i.a.) into mouse knee joints to induce reactive or gouty arthritis. Joint swelling, articular cell infiltration, and synovial cytokines were evaluated 25 hours and 4 hours following zymosan or MSU challenge, respectively. OLT1177 was administrated intraperitoneally by oral gavage or in the food by an OLT1177-enriched diet.
OLT1177 reduced zymosan-induced joint swelling (p < 0.001), cell influx (p < 0.01), and synovial levels of interleukin (IL)-1β, IL-6, and chemokine (C-X-C motif) ligand 1 (CXCL1) (p < 0.05), respectively, when compared with vehicle-treated mice. Plasma OLT1177 levels correlated (p < 0.001) dose-dependently with reduction in joint inflammation. Treatment of mice with OLT1177 limited MSU crystal articular inflammation (p > 0.0001), which was associated with decreased synovial IL-1β, IL-6, myeloperoxidase, and CXCL1 levels (p < 0.01) compared with vehicle-treated mice. When administrated orally 1 hour after MSU challenge, OLT1177 reduced joint inflammation, processing of IL-1β, and synovial phosphorylated c-Jun N-terminal kinase compared with the vehicle group. Mice were fed an OLT1177-enriched diet for 3 weeks and then challenged i.a. with MSU crystals. Joint swelling, synovial IL-1β, and expression of Nlrp3 and Il1b were significantly reduced in synovial tissues in mice fed an OLT1177-enriched diet when compared with the standard diet group.
Oral OLT1177 is highly effective in ameliorating reactive as well as gouty arthritis.
NLRP3 炎性小体的激活在痛风中放大了炎症反应，并介导了进一步的损伤。在本研究中，我们评估了 OLT1177 的治疗效果，OLT1177 是一种口服活性 NLRP3 炎性小体抑制剂，在人体中是安全的，用于小鼠急性关节炎模型。
将酵母聚糖或单钠尿酸盐 (MSU) 晶体关节内注射到小鼠膝关节中，以诱导反应性或痛风性关节炎。分别在酵母聚糖或 MSU 挑战后 25 小时和 4 小时评估关节肿胀、关节细胞浸润和滑膜细胞因子。OLT1177 通过口服灌胃或富含 OLT1177 的饮食进行腹腔内给药。
与 vehicle 处理的小鼠相比，OLT1177 分别降低了酵母聚糖诱导的关节肿胀（p < 0.001）、细胞浸润（p < 0.01）和滑膜白细胞介素 (IL)-1β、IL-6 和趋化因子 (C-X-C 基序) 配体 1 (CXCL1) 水平（p < 0.05）。血浆 OLT1177 水平与关节炎症的减轻呈剂量依赖性相关（p < 0.001）。用 OLT1177 治疗的小鼠限制了 MSU 晶体关节炎症（p > 0.0001），与 vehicle 处理的小鼠相比，滑膜白细胞介素 (IL)-1β、IL-6、髓过氧化物酶和 CXCL1 水平降低（p < 0.01）。与 MSU 挑战后 1 小时给予 OLT1177 相比，OLT1177 降低了关节炎症、IL-1β 的加工以及滑膜磷酸化 c-Jun N 末端激酶的水平。将小鼠用富含 OLT1177 的饮食喂养 3 周，然后用 MSU 晶体关节内注射。与标准饮食组相比，富含 OLT1177 的饮食组小鼠的关节肿胀、滑膜白细胞介素 (IL)-1β 以及 Nlrp3 和 Il1b 的表达均显著降低。
口服 OLT1177 可有效改善反应性和痛风性关节炎。
