Neuroprotective and axon growth-promoting effects following inflammatory stimulation on mature retinal ganglion cells in mice depend on ciliary neurotrophic factor and leukemia inhibitory factor.
After optic nerve injury retinal ganglion cells (RGCs) normally fail to regenerate axons in the optic nerve and undergo apoptosis. However, lens injury (LI) or intravitreal application of zymosan switch RGCs into an active regenerative state, enabling these neurons to survive axotomy and to regenerate axons into the injured optic nerve. Several factors have been proposed to mediate the beneficial effects of LI. Here, we investigated the contribution of glial-derived ciliary neurotrophic factor (CNTF) to LI-mediated regeneration and neuroprotection using wild-type and CNTF-deficient mice. In wild-type mice, CNTF expression was strongly upregulated in retinal astrocytes, the JAK/STAT3 pathway was activated in RGCs, and RGCs were transformed into an active regenerative state after LI. Interestingly, retinal LIF expression was correlated with CNTF expression after LI. In CNTF-deficient mice, the neuroprotective and axon growth-promoting effects of LI were significantly reduced compared with wild-type animals, despite an observed compensatory upregulation of LIF expression in CNTF-deficient mice. The positive effects of LI and also zymosan were completely abolished in CNTF/LIF double knock-out mice, whereas LI-induced glial and macrophage activation was not compromised. In culture CNTF and LIF markedly stimulated neurite outgrowth of mature RGCs. These data confirm a key role for CNTF in directly mediating the neuroprotective and axon regenerative effects of inflammatory stimulation in the eye and identify LIF as an additional contributing factor.
Leibinger
Marco
M
Department of Experimental Neurology, University of Ulm, 89081 Ulm, Germany.
Müller
Adrienne
A
Andreadaki
Anastasia
A
Hauk
Thomas G
TG
Kirsch
Matthias
M
Fischer
Dietmar
D
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000276:immunology* / Q000502:physiology*; D002478:Cells, Cultured; D002491:Central Nervous System Agents / Q000633:toxicity; D020934:Ciliary Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D053612:Janus Kinases / Q000378:metabolism; D007908:Lens, Crystalline / Q000293:injuries; D053605:Leukemia Inhibitory Factor / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009416:Nerve Regeneration / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D016501:Neurites / Q000276:immunology / Q000502:physiology; D009457:Neuroglia / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D020221:Optic Nerve Injuries / Q000276:immunology / Q000503:physiopathology; D012160:Retina / Q000187:drug effects / Q000276:immunology / Q000503:physiopathology; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000276:immunology* / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D015054:Zymosan / Q000633:toxicity
D002491:Central Nervous System Agents; D020934:Ciliary Neurotrophic Factor; D053605:Leukemia Inhibitory Factor; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015054:Zymosan; D053612:Janus Kinases