Department of Neurology, Beijing Chaoyang Hospital, Capital Medical University, No. 5 Jingyuan Road, Shijingshan District, Beijing, 100043, China.
Mol Biol Rep. 2021 Apr;48(4):3475-3484. doi: 10.1007/s11033-021-06339-4. Epub 2021 Apr 26.
Ischemia-reperfusion frequently occurs in ischemic cerebral vascular disease, during which the inflammatory signaling plays essential roles. The aim of this study was to discover the efficacy of the antibody to a key immune cytokine IL-23 (anti-IL-23) for the therapy of cerebral ischemia-reperfusion injury. We established the cerebral ischemia-reperfusion injury model by middle cerebral artery occlusion (MCAO). Anti-IL-23 injection attenuated lesions indicated by histology study. RT-PCR and Western blot were employed to detect the mRNA and protein expression of JAK2 and STAT3 after anti-IL-23 treatment. ELISA was utilized to measure the levels of MDA (malondialdehyde) and superoxide dismutase (SOD). Moreover, curcumin and IL-6 were implicated in the endogenous intervention of IL-23 signaling in vivo. Our data demonstrated that the treatment of anti-IL-23 might transcriptionally activate the classic immune pathway in the brain. Anti-IL-23 augmented phosphorylation levels of both JAK2 and STAT3, suggesting the amplification signaling of JAK/STAT after exogenous IL-23 intervention. Anti-IL-23 reduced ROS molecules of STAT downstream in the serum and brain. It also alleviated the injury by bringing down levels of MDA and SOD in the serum. JAK2 inhibitor could abolish the effect of anti-IL-23 whereas JAK3 ameliorated the injury. The combination of anti-IL-23 and JAK3i could reduce infarct volume more effectively. In summary, this study indicated that anti-IL-23 had protective effects against cerebral ischemia-reperfusion injury by targeting the immune specific JAK2-STAT3 in JAK/STAT pathway.
缺血再灌注经常发生在缺血性脑血管病中，在此过程中炎症信号发挥着重要作用。本研究旨在探讨抗白细胞介素 23（抗-IL-23）抗体对缺血性再灌注损伤的治疗作用。我们通过大脑中动脉闭塞（MCAO）建立了脑缺血再灌注损伤模型。抗-IL-23 注射减轻了组织学研究表明的病变。采用 RT-PCR 和 Western blot 检测抗-IL-23 治疗后 JAK2 和 STAT3 的 mRNA 和蛋白表达。采用 ELISA 法测定丙二醛（MDA）和超氧化物歧化酶（SOD）水平。此外，体内 IL-23 信号的内源性干预涉及姜黄素和 IL-6。我们的数据表明，抗-IL-23 治疗可能会在大脑中转录激活经典免疫途径。抗-IL-23 增强了 JAK2 和 STAT3 的磷酸化水平，表明外源性 IL-23 干预后 JAK/STAT 信号的放大。抗-IL-23 降低了血清和大脑中 STAT 下游的 ROS 分子。它还通过降低血清中 MDA 和 SOD 的水平减轻了损伤。JAK2 抑制剂可以消除抗-IL-23 的作用，而 JAK3 则可以改善损伤。抗-IL-23 和 JAK3i 的联合使用可以更有效地减少梗死体积。总之，本研究表明，抗-IL-23 通过靶向 JAK/STAT 通路中的免疫特异性 JAK2-STAT3，对缺血性再灌注损伤具有保护作用。
