School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou 510006, PR China.
Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, PR China.
Mol Immunol. 2019 Jan;105:76-85. doi: 10.1016/j.molimm.2018.10.015. Epub 2018 Nov 27.
Activation of NLRP3 inflammasomes is crucial in the pathological process of Ulcerative colitis (UC), which could be negatively regulated by PINK1/Parkin-driven mitophagy. Palmatine is a herb derived isoquinoline alkaloid with potent anti-inflammatory and anti-bacteria activities. In present study, we evaluated the effect of palmatine on dextran sulfate sodium (DSS)-induced mice colitis and examined whether its effect is exerted by promoting mitophagy-mediated NLRP3 inflammasome inactivation. The result showed that palmatine (40, 100 mg/kg) significantly prevented bodyweight loss and colonic shortening in DSS mice, and reduced the disease activity index and histopathologic score. The levels of MPO, IL-1β, TNF-α and the number of F4/80+ cells in colon of DSS mice were remarkably decreased by palmatine. Moreover, palmatine suppressed NLRP3 inflammasomes activation, but enhanced the expression of the mitophagy-related proteins involving LC3, PINK1 and Parkin in colonic tissue of DSS mice. These effects was consistent with the in vitro data revealing that palmatine inhibited the activation of NLRP3 inflammasomes, while promoted the expression and mitochondrial recruitment of PINK1 and Parkin in THP-1 cell differentiated macrophages. Furthermore, the effect of palmatine on THP-1 cells was neutralized by a mitophagy inhibitor Cyclosporin A (CsA) and PINK1-siRNA. In parallel, CsA significantly attenuated the therapeutic effect of palmatine in DSS mice, illustrating that the anti-colitis effect of palmatine is closely related to mitophagy. Taken together, the current results demonstrated that palmatine protected mice against DSS-induced colitis by facilitating PINK1/Parkin-driven mitophagy and thus inactivating NLRP3 inflammasomes in macrophage.
NLRP3 炎性小体的激活在溃疡性结肠炎（UC）的病理过程中至关重要，其可被 PINK1/Parkin 驱动的线粒体自噬负向调节。黄连碱是一种具有强大抗炎和抗菌活性的植物衍生异喹啉生物碱。在本研究中，我们评估了黄连碱对葡聚糖硫酸钠（DSS）诱导的小鼠结肠炎的作用，并研究了其作用是否通过促进线粒体自噬介导的 NLRP3 炎性小体失活来发挥。结果表明，黄连碱（40、100mg/kg）可显著防止 DSS 小鼠体重减轻和结肠缩短，并降低疾病活动指数和组织病理学评分。DSS 小鼠结肠中的 MPO、IL-1β、TNF-α 水平和 F4/80+细胞数量明显减少。此外，黄连碱抑制 NLRP3 炎性小体的激活，但增强了 DSS 小鼠结肠组织中涉及 LC3、PINK1 和 Parkin 的线粒体自噬相关蛋白的表达。这些作用与体外数据一致，表明黄连碱抑制 NLRP3 炎性小体的激活，同时促进 THP-1 细胞分化的巨噬细胞中 PINK1 和 Parkin 的表达和线粒体募集。此外，用线粒体自噬抑制剂环孢菌素 A（CsA）和 PINK1-siRNA 中和了黄连碱对 THP-1 细胞的作用。平行地，CsA 显著减弱了黄连碱在 DSS 小鼠中的治疗作用，表明黄连碱的抗结肠炎作用与线粒体自噬密切相关。综上所述，当前的结果表明，黄连碱通过促进 PINK1/Parkin 驱动的线粒体自噬来保护小鼠免受 DSS 诱导的结肠炎，从而使巨噬细胞中的 NLRP3 炎性小体失活。
