Leukemia Inhibitory Factor Extends the Lifespan of Injured Photoreceptors<i>In Vivo</i>

Joly, Sandrine; Lange, Christina; Thiersch, Markus; Samardzija, Marijana; Grimm, Christian

doi:10.1523/jneurosci.5114-08.2008

Cited by 119 publications

(183 citation statements)

References 42 publications

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“…This result suggests a positive feedback loop whereby gp130-mediated cell signaling events in rod cells further strengthen the initial CNTF-dependent Müller cell activation. Our quantitative PCR (qPCR) results show that hCNTF significantly enhances EDN2 mRNA expression, thus supporting the participation of exogenous hCNTF in this positive feed-forward signaling loop between Müller glia and photoreceptors (22,45,46). In addition to promoting EDN2 expression, hCNTF also stimulated expression of BDNF and possibly fibroblast growth factor 2 (FGF2), both of which can act as trophic factors on multiple cell types.…”

Section: Discussionsupporting

confidence: 66%

“…In the zebrafish and chicken, Müller glia have been identified as a source of endogenous stem cells able to repair damaged retinas (40)(41)(42). It is also known that Müller glia in the mature retina produce multiple signaling molecules that could critically influence retinal neuronal activity, survival, and repair (22,(43)(44)(45). In this study, we provide genetic evidence that the protection of photoreceptors by exogenous hCNTF relies on initial signaling through the gp130 receptor in Müller glia.…”

Section: Discussionmentioning

confidence: 99%

“…Injured photoreceptor-derived endothelin2 (EDN2) acts on its receptor EDNRb expressed by Müller glia (46). Furthermore, EDN2 can induce Müller glia to produce LIF, which acts as a chief neuroprotective agent in the lightinduced and inherited retinal degeneration models (22,45). Using cell-specific gp130 deletion, we also demonstrated that CNTF-dependent photoreceptor survival in the rds/P216L RP model relies on gp130 expressed by rod cells themselves.…”

Section: Discussionmentioning

confidence: 99%

“…Binding of CNTF to its receptor complex activates the Jak-STAT (16), the ERK (17), and the PI3K (18) pathways. In developing and mature rodent retinas, the CNTF family of cytokines stimulates Jak-STAT and ERK signaling (19)(20)(21)(22)(23). Previous studies have revealed that the dosage and duration of CNTF treatment critically affect the function of rescued neurons.…”

mentioning

confidence: 99%

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CNTF-mediated protection of photoreceptors requires initial activation of the cytokine receptor gp130 in Müller glial cells

Rhee¹,

Nusinowitz²,

Chao³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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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...

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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

CNTF-mediated protection of photoreceptors requires initial activation of the cytokine receptor gp130 in Müller glial cells

Rhee¹,

Nusinowitz²,

Chao³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…In both inherited and stress-induced retinal degeneration models, photoreceptors sharply increase the expression of endothelin 2 (End2), which is thought to induce Müller glial cells to secrete a number of neuroprotective factors, including leukemia inhibitory factor (LIF) and fibroblast growth factor 2 (FGF2) (10,14,27). This led to significant elevation of extracellular signal-regulated kinase (ERK), Stat3, and AKT phosphorylation in the retina (14,32). In the LIF knockout mice, however, the neuroprotective function of Müller glial cells is lost and End2/ FGF2/Stat3/AKT signaling is not upregulated (14).…”

mentioning

confidence: 99%

Loss of Shp2-Mediated Mitogen-Activated Protein Kinase Signaling in Müller Glial Cells Results in Retinal Degeneration

Cai

Simons

et al. 2011

Molecular and Cellular Biology

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Involvement of gp130‐associated cytokine signaling in Müller cell activation following optic nerve lesion

Kirsch

Trautmann

Ernst

et al. 2010

Glia

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Ciliary neurotrophic factor (CNTF) and the related cytokine leukemia inhibitory factor (LIF) have been implicated in regulating astrogliosis following CNS lesions. Application of the factors activates astrocytes in vivo and in vitro, and their expression as well as their receptors is upregulated after brain injury. Here, we investigated their function by studying Müller cell activation induced by optic nerve crush in CNTF- and LIF-deficient mice, and in animals with deficiencies in cytokine signaling pathways. In the retina of CNTF(-/-) mice, basal GFAP expression was reduced, but unexpectedly, injury-induced upregulation in activated Müller cells was increased during the first 3 days after lesion as compared to wild-type animals and this corresponded with higher phosphorylation level of STAT3, an indicator of cytokine signaling. The observation that LIF expression was strongly upregulated in CNTF(-/-) mice but not in wild-type animals following optic nerve lesion provided a possible explanation. In fact, additional ablation of the LIF gene in CNTF/LIF double knockout mice almost completely abolished early lesion-induced GFAP upregulation in Müller cells and STAT3 phosphorylation. Early Müller cell activation was also eliminated in LIF(-/-) mice, despite normal CNTF levels, as well as in mutants deficient in gp130/JAK/STAT signaling and in conditional STAT3 knockout mice. Our results demonstrate that LIF signaling via the gp130/JAK/STAT3 pathway is required for the initiation of the astrogliosis-like reaction of retinal Müller cells after optic nerve injury. A potential role of CNTF was possibly masked by a compensatory increase in LIF signaling in the absence of CNTF.

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Leukemia Inhibitory Factor Extends the Lifespan of Injured PhotoreceptorsIn Vivo

Cited by 119 publications

References 42 publications

CNTF-mediated protection of photoreceptors requires initial activation of the cytokine receptor gp130 in Müller glial cells

CNTF-mediated protection of photoreceptors requires initial activation of the cytokine receptor gp130 in Müller glial cells

Loss of Shp2-Mediated Mitogen-Activated Protein Kinase Signaling in Müller Glial Cells Results in Retinal Degeneration

Involvement of gp130‐associated cytokine signaling in Müller cell activation following optic nerve lesion

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