한빛사논문
Abstract
Kun Do Rheea, Steven Nusinowitza, Kevin Chaoa, Fei Yua, Dean Boka,b, and Xian-Jie Yanga,c,1
aJules Stein Eye Institute, Department of Ophthalmology,
bDepartment of Neurobiology, and
cMolecular Biology Institute, University of California, Los Angeles, CA 90095
Significance
The cytokine CNTF has been approved by the FDA as a neuroprotective treatment for major retinal degenerative diseases. However, the mechanism of CNTF-triggered protection and CNTF-responsive cells in the retina remains unknown. Using molecular genetic analyses in a retinal degeneration mouse model, we identify the Muller glial cell as the direct initial target of exogenous CNTF signals. We provide evidence that CNTF signals stimulate a Muller glia and photoreceptor intercellular signaling loop involved in neuronal survival. Nonetheless, despite the marked improvement in photoreceptor morphology and survival, CNTF treatment does not result in a corresponding improvement of visual function. These results provide insight into the mechanism of CNTF action in the diseased retinas relevant to its clinical applications.
Abstract
Ciliary neurotrophic factor (CNTF) acts as a potent neuroprotective agent in multiple retinal degeneration animal models. Recently, CNTF has been evaluated in clinical trials for the inherited degenerative disease retinitis pigmentosa (RP) and for dry age-related macular degeneration (AMD). Despite its potential as a broad-spectrum therapeutic treatment for blinding diseases, the target cells of exogenous CNTF and its mechanism of action remain poorly understood. We have shown previously that constitutive expression of CNTF prevents photoreceptor death but alters the retinal transcriptome and suppresses visual function. Here, we use a lentivirus to deliver the same secreted human CNTF used in clinical trials to a mouse model of RP. We found that low levels of CNTF halt photoreceptor death, improve photoreceptor morphology, and correct opsin mislocalization. However, we did not detect corresponding improvement of retinal function as measured by the electroretinogram. Disruption of the cytokine receptor gp130 gene in Muller glia reduces CNTF-dependent photoreceptor survival and prevents phosphorylation of STAT3 and ERK in Muller glia and the rest of the retina. Targeted deletion of gp130 in rods also demolishes neuroprotection by CNTF and prevents further activation of Muller glia. Moreover, CNTF elevates the expression of LIF and endothelin 2, thus positively promoting Müller and photoreceptor interactions. We propose that exogenous CNTF initially targets Muller glia, and subsequently induces cytokines acting through gp130 in photoreceptors to promote neuronal survival. These results elucidate a cellular mechanism for exogenous CNTF-triggered neuroprotection and provide insight into the complex cellular responses induced by CNTF in diseased retinas.
1To whom correspondence should be addressed.
Author contributions: K.D.R. and X.-J.Y. designed research; K.D.R., S.N., K.C., and D.B. performed research; K.D.R., S.N., F.Y., D.B., and X.-J.Y. analyzed data; and K.D.R. and X.-J.Y. wrote the paper.
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