Astrocyte-derived CNTF switches mature RGCs to a regenerative state following inflammatory stimulation.
Retinal ganglion cells (RGCs) normally fail to regenerate injured axons and undergo apoptosis soon after injury. We have recently shown that lens injury (LI) or intravitreally applied zymosan allow RGCs to survive axotomy and regenerate axons in the injured optic nerve. Activated macrophages and oncomodulin have been suggested to be the principal mediators of this phenomenon. However, several lines of evidence show that macrophage-derived factors alone cannot account for all the beneficial effects of intraocular inflammation. We show here that LI or zymosan induce upregulation of ciliary neurotrophic factor (CNTF) in retinal astrocytes and release CNTF independent of macrophages and activate the transcription factor signal transducers and activators of transcription 3 (STAT3) in RGCs. Levels of CNTF expressed in retinal glia and STAT3 activation in RGC were correlated with the time course of RGCs switching to an active regenerative state. Intravitreal injections of antibodies against CNTF or a Janus-kinase inhibitor compromised the beneficial effects of LI, whereas an antiserum against oncomodulin was ineffective. Like the action of CNTF, the effects of LI were potentiated by drugs that increase intracellular cAMP levels, resulting in strong axon regeneration in vivo. These data indicate that astrocyte-derived CNTF is a major contributor to the neuroprotective and axon-growth-promoting effects of LI and zymosan. These findings could lead to the development of a therapeutic principle for promoting axon regeneration in the CNS as a whole.
Müller
Adrienne
A
Department of Experimental Neurology, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
Hauk
Thomas G
TG
Fischer
Dietmar
D
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001369:Axons / Q000502:physiology; D002478:Cells, Cultured; D020934:Ciliary Neurotrophic Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D003459:Crystallins / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D053612:Janus Kinases / Q000502:physiology; D007908:Lens, Crystalline / Q000293:injuries; D008264:Macrophages / Q000502:physiology; D009416:Nerve Regeneration / Q000187:drug effects; D020221:Optic Nerve Injuries / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000502:physiology; D015398:Signal Transduction; D046509:Tissue Culture Techniques; D015054:Zymosan / Q000494:pharmacology
D020934:Ciliary Neurotrophic Factor; D003459:Crystallins; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D015054:Zymosan; D053612:Janus Kinases