| First Author | Guo S | Year | 2015 |
| Journal | J Neurosci | Volume | 35 |
| Issue | 34 | Pages | 12047-62 |
| PubMed ID | 26311783 | Mgi Jnum | J:226167 |
| Mgi Id | MGI:5696447 | Doi | 10.1523/JNEUROSCI.1800-15.2015 |
| Citation | Guo S, et al. (2015) Oncostatin M Confers Neuroprotection against Ischemic Stroke. J Neurosci 35(34):12047-62 |
| abstractText | 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 OSMRbeta in the setting of ischemic stroke. Using gain- and loss-of-function approaches, we demonstrated that decreased neuronal OSMRbeta expression results in deteriorated stroke outcomes but that OSMRbeta 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/OSMRbeta activate the JAK2/STAT3 prosurvival signaling pathway. Collectively, these data support that human OSM may represent a promising drug candidate for stroke treatment. SIGNIFICANCE STATEMENT: OSM, a member of the gp130 cytokine family, regulates neuronal function and survival. OSM engages a second receptor, either LIFRalpha or OSMRbeta, before recruiting gp130. However, it is not clear whether OSM/OSMRbeta 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 OSMRbeta in both mouse and rat stroke models to demonstrate that OSMRbeta 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. |
