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V. P. Sarthy, W. Xu, V. Dudley, M. Brooks, R. Khanna, J. Roger, A. Swaroop; Müller Cell/Microglia Interactions in CNTF-Mediated Photoreceptor Neuroprotection. Invest. Ophthalmol. Vis. Sci. 2009;50(13):694.
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© ARVO (1962-2015); The Authors (2016-present)
Ciliary neurotrophic factor (CNTF) has been reported to be the most effective and mutation-independent, neuroprotective agent known to retard retinal degeneration in several animal models of retinitis pigmentosa. Recently, a phase I clinical trial demonstrated the safety of chronic CNTF delivery in patients with retinitis pigmentosa, and phase II trials are underway for patients with RP and dry AMD. The molecular mechanisms underlying CNTF-mediated neuroprotection are not understood. Available experimental evidence suggests that the CNTF effect on photoreceptors is indirect, and that CNTF acts by stimulating Müller cells. The goal of the present study is to elucidate the nature of this neuroprotective signaling.
We have investigated this question directly by microarray analysis of GFP+-Müller cells flow-sorted from CNTF-injected and PBS-injected eyes. Microarray data were validated by qPCR and ELISA.
We found that 1907 transcripts were changed at least two-fold, following CNTF treatment. Among these, 1324 transcripts were upregulated 2- to 17-fold, and 583 were downregulated 2- to 7-fold. Ingenuity Pathway Analysis of the microarray data showed that the up- and down-regulated genes fell into several functional types including as growth factors, cytokines, kinases, transporters, ion channels, etc. Also, more anti-apoptotic than pro-apoptotic genes were upregulated in CNTF-treated Müller cells. Several genes that have been reported to be upregulated in ‘reactive’ Müller cells such as genes encoding - CCAT enhancer binding protein, GFAP, ceruloplasmin, endothelin 2, Fibroblast Factor 2, Oncostatin M receptor and SOCS-3, were also activated by CNTF treatment. Interestingly, a large number of proinflammatory chemokine genes were upregulated in these Müller cells. Finally, transcriptional analysis of flow-sorted microglia cells showed that TNF-a, Dap12 and Clec7a genes were upregulated indicating microglial activation in CNTF-treated eyes.
Our studies lead to the surprising finding that CNTF treatment leads to transcriptional activation proinflammatory cytokine genes in Müller cells that activate retinal microglia. Activated retinal microglia in turn might modulate CNTF-mediated neuroprotection.
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