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 agerelated 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.C iliary neurotrophic factor (CNTF) belongs to a small subfamily of cytokines and has long been recognized as a potent neuroprotective molecule in the vertebrate retina (1). Enhancement of photoreceptor survival by CNTF has been demonstrated in multiple animal models of retinal degeneration, ranging from zebrafish to canine (2). Interestingly, CNTF is effective in rescuing retinal degeneration due to various causes, including mutations in genes expressed by photoreceptors or the retinal pigment epithelium (RPE), as well as those induced by strong light, neurotoxins, or antibodies. In addition, CNTF prolongs the survival of retinal ganglion cells (3-5) and promotes axonal growth in optic nerve crush or transection models (6-8). Furthermore, CNTF may affect the physiology and survival of RPE cells (9, 10), which are critical in normal vision and retinal degenerative diseases. Based on its significant and broad neuroprotective effects in damaged retinas, a secreted form of human CNTF delivered from an encapsulated cell device has been tested in clinical trials and approved by the Food and Drug Administration (FDA) to treat retinitis pigmentosa (RP) and geographic atrophy (GA), a subset of age-related macular degeneration (AMD) (11-14). However, despite its clinical signifi...

Leptin and IL-6 Family Cytokines Synergize to Stimulate Müller Glia Reprogramming and Retina Regeneration

“…It is interesting that IL-6 family cytokines and p-Stat3 signaling stimulate MG to reprogram and generate progenitors in the zebrafish retina, while in birds and mammals these signaling molecules appear to act on MG to stimulate a gliotic response that functions to protect the retina from damage (Fischer et al, 2004a; Fischer et al, 2004b; Peterson et al, 2000; Rhee et al, 2013; Xue et al, 2011). In fish, Jak/Stat signaling may collaborate with other signaling pathways to stimulate retina regeneration while in mammals these additional pathways may not be regulated in a similar fashion.…”

Glia–neuron interactions in the mammalian retina

“…Interestingly, the transcript profiles of Müller cells and astrocytes are similar although they are derived from distinct cell lineages (Xue et al, 2011). Exogenous CNTF initially targets Müller glia and they trigger a reaction that induces the production of cytokines that act through gp130 in photoreceptors to promote neuronal survival (Rhee et al, 2013). Indeed, CNTF not only reduces the death of photoreceptors but it also rescues retinal function (Heiduschka et al, 2013).…”

Functional architecture of the retina: Development and disease

“…Behavioral paradigms such as environmental enrichment that increase in vivo levels of these neurotrophic factors, exert protective effects against mouse photoreceptor degeneration (Barone et al, 2012). The mechanism of action of CNTF as elucidated in mouse retina initially involves interaction with the cytokine receptors gp130 on Müller glia cells, since their genetic disruption abolishes CNTF neuroprotection (Rhee et al, 2013). Because photoreceptors usually die by apoptosis, neuroprotection has been induced by inhibiting the apoptotic signaling pathway mediated by the phospholipid ceramide in light-induced photoreceptor degeneration models (Chen et al, 2013a), and in the rd10 mouse model for RP (Strettoi et al, 2010).…”