RRC ID 34765
Author Guo S, Li ZZ, Gong J, Xiang M, Zhang P, Zhao GN, Li M, Zheng A, Zhu X, Lei H, Minoru T, Li H.
Title Oncostatin M Confers Neuroprotection against Ischemic Stroke.
Journal J. Neurosci.
Abstract UNLABELLED: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.
SIGNIFICANCE STATEMENT: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.
Volume 35(34)
Pages 12047-62
Published 2015-8-26
DOI 10.1523/JNEUROSCI.1800-15.2015
PII 35/34/12047
PMID 26311783
MeSH Animals Brain Ischemia / metabolism* Brain Ischemia / pathology Brain Ischemia / prevention & control* Female Humans Male Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Oncostatin M / biosynthesis* Oncostatin M Receptor beta Subunit / biosynthesis* Pregnancy Rats Rats, Sprague-Dawley Stroke / metabolism* Stroke / pathology Stroke / prevention & control*
IF 5.971
Times Cited 5
WOS Category NEUROSCIENCES
Resource
Mice B6.129S-Osmr<tm1Mtan>(RBRC02711)