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The Journal of Neuroscience, March 15, 2003, 23(6):2284
Macrophage-Derived Factors Stimulate Optic Nerve Regeneration
Yuqin Yin1, 2, *, Qi Cui4, *, Yiming Li1, 2, Nina Irwin1, 2, Dietmar Fischer1, 2, Alan R. Harvey4, and Larry I. Benowitz1, 2, 3 1 Laboratories for Neuroscience Research in Neurosurgery, Children's Hospital, Boston, Massachusetts 02115, 2 Department of Surgery and 3 Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115, and 4 School of Anatomy and Human Biology and Western Australian Institute for Medical Research, University of Western Australia, Crawley, WA 6009, Australia
After optic nerve injury in mature mammals, retinal ganglion cells (RGCs) are normally unable to regenerate their axons and undergo delayed apoptosis. However, if the lens is damaged at the time of nerve injury, many RGCs survive axotomy and regenerate their axons into the distal optic nerve. Lens injury induces macrophage activation, and we show here that factors secreted by macrophages stimulate RGCs to regenerate their axons. When macrophages were activated by intravitreal injections of Zymosan, a yeast cell wall preparation, the number of RGC axons regenerating into the distal optic nerve was even greater than after lens injury. These effects were further enhanced if Zymosan was injected 3 d after nerve crush. In a grafting paradigm, intravitreal Zymosan increased the number of RGCs that regenerated their axons through a 1.5 cm peripheral nerve graft twofold relative to uninjected controls and threefold if injections were delayed 3 d. In cell culture, media conditioned by activated macrophages stimulated adult rat RGCs to regenerate their axons; this effect was potentiated by a low molecular weight factor that is constitutively present in the vitreous humor. After gel-filtration chromatography, macrophage-derived proteins
30 kDa were found to be toxic to RGCs, whereas proteins <30 kDa reversed this toxicity and promoted axon regeneration. The protein(s) that stimulated axon growth is distinct from identified polypeptide trophic factors that were tested. Thus, macrophages produce proteins with both positive and negative effects on RGCs, and the effects of macrophages can be optimized by the timing of their activation.
Key words: retina; ganglion cell; GAP-43; monocyte; trophic factor; cell culture
* Y.Y. and Q.C. contributed equally to this work.
Copyright © 2003 Society for Neuroscience 0270-6474/03/2362284-10$05.00/0
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