Central Laboratory, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China.
Beijing University of Chinese Medicine, Beijing, China.
Int Immunopharmacol. 2020 Jul;84:106547. doi: 10.1016/j.intimp.2020.106547. Epub 2020 Apr 30.
The nod-like receptor protein 3 (NLRP3) inflammasome has a critical role in cerebral ischemia. Autophagy may cause microglial inflammatory response or stimulate microglial function. The evidences clarify a direct crosstalk between autophagy and NLRP3. Geniposide could protect neurons or PC-12 cells against cerebral ischemic injury. However, a detailed understanding of molecular mechanisms on geniposide is still unclear. This study aimed to evaluate whether geniposide could inhibit the expression and activation of NLRP3 inflammasome in BV-2 microglial cells following oxygen-glucose deprivation/reoxygenation (OGD/R) and assessed whether autophagy is involved in this process. We used OGD/R model in BV2 microglial cells in order to mimic the ischemic reperfusion injury. The NLRP3 shRNA and autophagy inhibitor (3-MA) were used to suppress NLRP3 inflammation activation and autophagy. The results demonstrated geniposide decreased cell death and the levels of NLRP3, ASC, cleaved- caspase-1 and IL-1β, whereas significantly increased the conversion of LC3 and Beclin-1 expression, decreased the expression of P62. Taken together, our results suggested that the effect of geniposide could be ascribed to the reduction of the level of inflammatory cytokines via inhibiting the activation and expression of NLRP3 inflammasome and increasing autophagic activity following OGD/R in BV-2 microglial cells. We provided a new understanding of geniposide in neuroprotection by activating autophagy and promoting anti-inflammation inhibiting NLRP3 inflammasome in microglial cells. It might be helpful for geniposide on effective therapeutic strategies in ischemic stroke.
核苷酸结合寡聚化结构域样受体蛋白 3（NLRP3）炎性小体在脑缺血中具有关键作用。自噬可能引起小胶质细胞炎症反应或刺激小胶质细胞功能。这些证据阐明了自噬与 NLRP3 之间的直接相互作用。京尼平苷可保护神经元或 PC-12 细胞免受脑缺血损伤。然而，对于京尼平苷的分子机制的详细了解仍不清楚。本研究旨在评估京尼平苷是否可以抑制氧葡萄糖剥夺/复氧（OGD/R）后 BV-2 小胶质细胞中 NLRP3 炎性小体的表达和激活，并评估自噬是否参与这一过程。我们使用 OGD/R 模型在 BV2 小胶质细胞中模拟缺血再灌注损伤。使用 NLRP3 shRNA 和自噬抑制剂（3-MA）抑制 NLRP3 炎症激活和自噬。结果表明，京尼平苷降低了细胞死亡和 NLRP3、ASC、裂解的 caspase-1 和 IL-1β的水平，而 LC3 和 Beclin-1 的转化显著增加，P62 的表达减少。综上所述，我们的结果表明，京尼平苷的作用可能归因于通过抑制 NLRP3 炎性小体的激活和表达以及在 BV-2 小胶质细胞中增加自噬活性来降低炎症细胞因子的水平。我们为京尼平苷通过激活自噬和促进抗炎症抑制小胶质细胞中的 NLRP3 炎性小体提供了一种新的神经保护作用机制。这可能有助于京尼平苷在缺血性中风的有效治疗策略上发挥作用。
