Chemotactic Effect of Ciliary Neurotrophic Factor on Macrophages in Retinal Ganglion Cell Survival and Axonal Regeneration

Cen, Ling-Ping; Luo, Jian-Min; Zhang, Chengwu; Fan, Yu; Song, Yue; So, Kwok‐Fai; Rooijen, Nico van; Pang, Chi Pui; Lam, Dennis Shun Chiu; Cui, Qing

doi:10.1167/iovs.06-0791

Cited by 74 publications

(60 citation statements)

References 45 publications

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“…Of note, CNTF was recently shown to act in part through an indirect mechanism in inducing RGCs to regenerate axons through a peripheral nerve graft. CNTF was found to stimulate macrophage activation, and its effects on regeneration were suppressed when macrophages were eliminated (27). It remains possible, however, that CNTF could contribute to the effects of intraocular inflammation in enhancing RGC survival (20,28).…”

Section: Discussionmentioning

confidence: 99%

Oncomodulin links inflammation to optic nerve regeneration

Yin¹,

Cui

Gilbert³

et al. 2009

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

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The inflammatory response that accompanies central nervous system (CNS) injury can affect neurological outcome in both positive and negative ways. In the optic nerve, a CNS pathway that normally fails to regenerate when damaged, intraocular inflammation causes retinal ganglion cells (RGCs) to switch into an active growth state and extend lengthy axons down the nerve. The molecular basis of this phenomenon is uncertain. A prior study showed that oncomodulin (Ocm), a Ca 2؉ -binding protein secreted by a macrophage cell line, is a potent axon-promoting factor for RGCs. However, it is not known whether Ocm contributes to the physiological effects of intraocular inflammation in vivo, and there are conflicting reports in the literature regarding its expression and significance. We show here that intraocular inflammation causes infiltrative cells of the innate immune system to secrete high levels of Ocm, and that agents that prevent Ocm from binding to its receptor suppress axon regeneration. These results were verified in different strains, species, and experimental models, and establish Ocm as a potent growth-promoting signal between the innate immune system and neurons in vivo.retina ͉ trophic factor

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Section: Discussionmentioning

confidence: 99%

Oncomodulin links inflammation to optic nerve regeneration

Yin¹,

Cui

Gilbert³

et al. 2009

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

Self Cite

177

186

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“…Others have suggested that proinflammatory agents cause CNTF to be secreted from retinal astrocytes and act as the primary mediator of optic nerve regeneration (Muller et al, 2007), but this appears unlikely in view of many studies that demonstrate that intraocularly injected CNTF has only a minor effect on axon regeneration in the mature visual system due to the developmental increase in expression of SOCS3, a suppressor of signaling through the Janus kinase (Jak)-signal transducers and activators of transcription (STAT) pathway (Cohen et al, 1994;Park et al, 2009;Smith et al, 2009;Qin et al, 2013). In one study in which high concentrations of CNTF were found to promote axon regeneration through a peripheral nerve graft, this effect was found to be secondary to the effect of CNTF in recruiting macrophages (Cen et al, 2007), but this issue has not been examined in other studies in which high intravitreal concentrations of CNTF or virally delivered CNTF was found to have some effect (Leaver et al, 2006;Pernet et al, 2013b). Another argument against CNTF or any other trophic factor playing a major role in mediating the effects of inflammation on optic nerve regeneration is the near-complete loss of regeneration seen when the effects of Ocm are blocked (Yin et al, 2009;Kurimoto et al, 2013).…”

Section: Oncomodulin As a Key Mediator Of Inflammation-induced Regenementioning

confidence: 99%

Inflammation and Optic Nerve Regeneration

et al. 2015

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“…2012; 53:6025-6034) DOI:10.1167/iovs.12-9898 R etinal diseases, such as glaucoma, age-related macular degeneration, and ischemia, are major causes of blindness due to retinal neural cell degeneration. Neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) 1,2 and ciliary derived neurotrophic factor (CNTF), 3,4 have been shown to be neuroprotective effectively in these disease models. Erythropoietin (EPO), which historically was best known for its hematopoietic properties, recently has been proved to exhibit neuroprotective effects on neurons in the retina and central nervous system.…”

Section: Discussionmentioning

confidence: 99%

Effects of Erythropoietin-Dextran Microparticle-Based PLGA/PLA Microspheres on RGCs

Xiao

Yang

Miao

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. We explored the neuroprotective effects of erythropoietin (EPO)-loaded dextran microparticle-based Poly(DLlactide-co-glycolide)/Poly(DL-lactide) (PLGA/PLA) microspheres (EPO-dextran PLGA/PLA microspheres) on retinal ganglion cells (RGCs) in optic nerve crush rats for a prolonged period of time.METHODS. EPO-dextran PLGA/PLA microspheres were prepared first by a novel solid-in-oil-in-water (S/O/W) technique. Then, the in vitro EPO release profile was assessed. Afterward, the bioactive effect of EPO released from EPO-dextran PLGA/PLA microspheres was explored in vitro on the retinal explants. Lastly, the neuroprotective effects of EPO-dextran PLGA/PLA microspheres on RGCs were evaluated in optic nerve crush rats with TUNEL staining for apoptotic RGCs. The level of glial fibrillary acidic protein (GFAP) expressed in retina was explored by immunohistochemistry staining. Survival RGCs were observed by DiI retrograde labeling using a DiI fluorescent tracer (1,1 0 -dioctadecyl-3,3,3 0 ,3 0 -tetramethylindocarbocyanine perchlorate). RESULTS.The results demonstrated that a sustained release of EPO from PLGA/PLA microspheres could last for at least 60 days. EPO released from the microspheres showed as efficaciously neuroregenerative as EPO protein solution on retinal explants (P ¼ 0.2554 for neurite density, P ¼ 0.1004 for neurite length). TUNEL staining revealed that EPO-dextran PLGA/PLA microspheres remarkably reduced RGCs death when compared to the control (untreated) group (P < 0.01 at five days and one week post-crush, P < 0.05 at two weeks post-crush). Increased GFAP expression in retina was reduced greatly in EPO-dextran PLGA/PLA microspheres-administrated rats two weeks post optic nerve crush. DiI retrograde labeling revealed that a single injection of EPO-dextran PLGA/PLA microspheres significantly promoted RGCs survival (P < 0.01 at four and eight weeks post-crush). CONCLUSIONS.A single intravitreal injection of EPO-dextran PLGA/PLA microspheres appeared to have a prolonged protective effect on RGCs in optic nerve crush rats. The PLGA/PLA microspheres may be a feasible protein delivery system, such as EPO, to intravitreal injection for retinal degeneration diseases. (Invest Ophthalmol Vis Sci. 2012; 53:6025-6034)

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Chemotactic Effect of Ciliary Neurotrophic Factor on Macrophages in Retinal Ganglion Cell Survival and Axonal Regeneration

Abstract: CNTF is a chemoattractant but not a proliferation enhancer for blood-derived macrophages, and blood-borne macrophages recruited into the eye by CNTF participate in RGC protection. This finding thus adds an important category to the existing understanding of the biological actions of CNTF.

Cited by 74 publications

References 45 publications

Oncomodulin links inflammation to optic nerve regeneration

Oncomodulin links inflammation to optic nerve regeneration

Inflammation and Optic Nerve Regeneration

Effects of Erythropoietin-Dextran Microparticle-Based PLGA/PLA Microspheres on RGCs

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