title: CNTF-mediated protection of photoreceptors requires initial activation of the cytokine receptor gp130 in Müller glial cells.
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 Müller glia reduces CNTF-dependent photoreceptor survival and prevents phosphorylation of STAT3 and ERK in Müller glia and the rest of the retina. Targeted deletion of gp130 in rods also demolishes neuroprotection by CNTF and prevents further activation of Müller 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 Müller 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.
authors.affiliation: Jules Stein Eye Institute, Department of Ophthalmology, Department of Neurobiology, and Molecular Biology Institute, University of California, Los Angeles, CA 90095.
authors.forename: Kun Do
authors.initials: KD
authors.lastname: Rhee
authors.forename: Steven
authors.initials: S
authors.lastname: Nusinowitz
authors.forename: Kevin
authors.initials: K
authors.lastname: Chao
authors.forename: Fei
authors.initials: F
authors.lastname: Yu
authors.forename: Dean
authors.initials: D
authors.lastname: Bok
authors.forename: Xian-Jie
authors.initials: XJ
authors.lastname: Yang
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D020934:Ciliary Neurotrophic Factor / Q000378:metabolism*; D050822:Cytokine Receptor gp130 / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D063928:Ependymoglial Cells / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D016086:Lentivirus; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D012162:Retinal Degeneration / Q000188:drug therapy* / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D020934:Ciliary Neurotrophic Factor; D050822:Cytokine Receptor gp130