Guo Sen, Li Zuo-Zhi, Gong Jun, Xiang Mei, Zhang Peng, Zhao Guang-Nian, Li Mingchang, Zheng Ankang, Zhu Xueyong, Lei Hao, Minoru Tanaka, Li Hongliang
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China.
Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100730, PR China, National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, PR China.
J Neurosci. 2015 Aug 26;35(34):12047-62. doi: 10.1523/JNEUROSCI.1800-15.2015.
Cell-surface receptors provide potential targets for the translation of bench-side findings into therapeutic strategies; however, this approach for the treatment of stroke is disappointing, at least partially due to an incomplete understanding of the targeted factors. Previous studies of oncostatin M (OSM), a member of the gp130 cytokine family, have been limited, as mouse models alone may not strongly resemble the human condition enough. In addition, the precise function of OSM in the CNS remains unclear. Here, we report that human OSM is neuroprotective in vivo and in vitro by recruiting OSMRβ in the setting of ischemic stroke. Using gain- and loss-of-function approaches, we demonstrated that decreased neuronal OSMRβ expression results in deteriorated stroke outcomes but that OSMRβ overexpression in neurons is cerebroprotective. Moreover, administering recombinant human OSM to mice before the onset of I/R showed that human OSM can be protective in rodent models of ischemic stroke. Mechanistically, OSM/OSMRβ activate the JAK2/STAT3 prosurvival signaling pathway. Collectively, these data support that human OSM may represent a promising drug candidate for stroke treatment.
OSM, a member of the gp130 cytokine family, regulates neuronal function and survival. OSM engages a second receptor, either LIFRα or OSMRβ, before recruiting gp130. However, it is not clear whether OSM/OSMRβ signaling is involved in neuroprotection in the setting of ischemic stroke. Recent studies show that, compared with mouse disease models, the OSM receptor system in rats more closely resembles that in humans. In the present study, we use genetic manipulations of OSMRβ in both mouse and rat stroke models to demonstrate that OSMRβ in neurons is critical for neuronal survival during cerebral ischemic/reperfusion. Interestingly, administration of human OSM also leads to improved stroke outcomes. Therefore, OSM may represent a promising drug candidate for stroke treatment.
细胞表面受体为将实验室研究结果转化为治疗策略提供了潜在靶点；然而，这种治疗中风的方法令人失望，至少部分原因是对靶向因子的理解不完整。以往对抑瘤素M（OSM）（gp130细胞因子家族成员）的研究有限，因为仅小鼠模型可能与人类情况的相似性不够强。此外，OSM在中枢神经系统中的精确功能仍不清楚。在此，我们报告人类OSM在缺血性中风情况下通过招募OSMRβ在体内和体外具有神经保护作用。使用功能获得和功能丧失方法，我们证明神经元OSMRβ表达降低会导致中风结果恶化，但神经元中OSMRβ过表达具有脑保护作用。此外，在缺血/再灌注发作前给小鼠注射重组人OSM表明，人OSM在缺血性中风的啮齿动物模型中具有保护作用。从机制上讲，OSM/OSMRβ激活JAK2/STAT3促生存信号通路。总体而言，这些数据支持人OSM可能是一种有前景的中风治疗候选药物。
OSM是gp130细胞因子家族成员，调节神经元功能和存活。OSM在招募gp130之前会结合第二个受体，即白血病抑制因子受体α（LIFRα）或OSMRβ。然而，尚不清楚OSM/OSMRβ信号是否参与缺血性中风情况下的神经保护。最近的研究表明，与小鼠疾病模型相比，大鼠中的OSM受体系统与人类中的更相似。在本研究中，我们在小鼠和大鼠中风模型中对OSMRβ进行基因操作，以证明神经元中的OSMRβ对脑缺血/再灌注期间的神经元存活至关重要。有趣的是，给予人OSM也会导致中风结果改善。因此，OSM可能是一种有前景的中风治疗候选药物。
