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Oncostatin M Confers Neuroprotection against Ischemic Stroke
- Source :
- The Journal of neuroscience : the official journal of the Society for Neuroscience. 35(34)
- Publication Year :
- 2015
-
Abstract
- 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 OSMR β 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.
- Subjects :
- Male
medicine.medical_treatment
Mice, Transgenic
Oncostatin M
Neuroprotection
Brain Ischemia
Brain ischemia
Rats, Sprague-Dawley
Mice
Pregnancy
medicine
Animals
Humans
STAT3
Stroke
Mice, Knockout
Oncostatin M Receptor beta Subunit
biology
business.industry
General Neuroscience
fungi
Articles
medicine.disease
Glycoprotein 130
Rats
Mice, Inbred C57BL
Cytokine
biology.protein
Female
Signal transduction
business
Neuroscience
Subjects
Details
- ISSN :
- 15292401
- Volume :
- 35
- Issue :
- 34
- Database :
- OpenAIRE
- Journal :
- The Journal of neuroscience : the official journal of the Society for Neuroscience
- Accession number :
- edsair.doi.dedup.....b859086ff45cec20e051e17b04a19f2d