| First Author | Rhee KD | Year | 2013 |
| Journal | Proc Natl Acad Sci U S A | Volume | 110 |
| Issue | 47 | Pages | E4520-9 |
| PubMed ID | 24191003 | Mgi Jnum | J:202986 |
| Mgi Id | MGI:5523733 | Doi | 10.1073/pnas.1303604110 |
| Citation | Rhee KD, et al. (2013) CNTF-mediated protection of photoreceptors requires initial activation of the cytokine receptor gp130 in Muller glial cells. Proc Natl Acad Sci U S A 110(47):E4520-9 |
| abstractText | 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 Muller 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. |
