Lens injury induced activation of retinal glia, and subsequent release of ciliary neurotrophic factor (CNTF) and leukaemia inhibitory factor (LIF) potently protect axotomised retinal ganglion cells from apoptosis and promotes axon regeneration in the injured optic nerve. The goal of the current study was to investigate if similar effects may also be applicable to rescue photoreceptors from degeneration in a model of retinitis pigmentosa. Lens injury was performed in the Royal College of Surgeons (RCS) rats at the age of one month. The survival of photoreceptors was evaluated histologically, and retinal function was analysed by electroretinography (ERG). Expression of CNTF was also analysed. Lens injury significantly enhanced the survival of photoreceptors 1 month after surgery compared to untreated controls, which was associated with an enhanced ERG response. In addition, lens injury significantly protected photoreceptors from degeneration in the contralateral eye, although to a much lesser extent. We could show that lens injury is sufficient to transiently delay the degeneration of photoreceptors in the RCS rat. The observed neuroprotective effects may be at least partially mediated by an upregulation of CNTF expression seen after lens injury. 1. Introduction It has recently been shown that lens injury or intravitreal applications of lens-derived β/γ-crystallins potently protect axotomised retinal ganglion cells (RGCs) from cell death and stimulate axon regeneration in the injured optic nerve [1–5]. All treatments induce an activation of retinal astrocytes and Müller cells, which subsequently upregulate and release the cytokines ciliary neurotrophic factor (CNTF) and leukaemia inhibitory factor (LIF) [6–10]. The strong neuroprotective effects of lens injury are completely absent in CNTF/LIF double knockout mice, demonstrating that both cytokines act as essential key mediators [9, 11]. Similar to these factors, interleukin 6 also promotes neuroprotection [12]. The purpose of the current study was to investigate whether lens injury is also sufficient to protect photoreceptors from degeneration. As a model, we chose the Royal College of Surgeons (RCS) rat, which is a commonly used model of retinal degeneration, in particular retinitis pigmentosa. The cells of the retinal pigment epithelium (RPE) are not capable of phagocytosing photoreceptor outer segments due to a mutation in the Mertk gene. This leads to a gradual degeneration of the photoreceptors starting at the time point of eye opening (i.e., approximately at P20) and being completed at the age of 3
References
[1]
D. Fischer, M. Pavlidis, and S. Thanos, “Cataractogenic lens injury prevents traumatic ganglion cell death and promotes axonal regeneration both in vivo and in culture,” Investigative Ophthalmology and Visual Science, vol. 41, no. 12, pp. 3943–3954, 2000.
[2]
S. Leon, Y. Yin, J. Nguyen, N. Irwin, and L. I. Benowitz, “Lens injury stimulates axon regeneration in the mature rat optic nerve,” The Journal of Neuroscience, vol. 20, no. 12, pp. 4615–4626, 2000.
[3]
D. Fischer, P. Heiduschka, and S. Thanos, “Lens-injury-stimulated axonal regeneration throughout the optic pathway of adult rats,” Experimental Neurology, vol. 172, no. 2, pp. 257–272, 2001.
[4]
B. Lorber, M. Berry, and A. Logan, “Lens injury stimulates adult mouse retinal ganglion cell axon regeneration via both macrophage- and lens-derived factors,” European Journal of Neuroscience, vol. 21, no. 7, pp. 2029–2034, 2005.
[5]
D. Fischer, T. G. Hauk, A. Müller, and S. Thanos, “Crystallins of the β/γ-superfamily mimic the effects of lens injury and promote axon regeneration,” Molecular and Cellular Neuroscience, vol. 37, no. 3, pp. 471–479, 2008.
[6]
A. Müller, T. G. Hauk, and D. Fischer, “Astrocyte-derived CNTF switches mature RGCs to a regenerative state following inflammatory stimulation,” Brain, vol. 130, no. 12, pp. 3308–3320, 2007.
[7]
S. Joly, C. Lange, M. Thiersch, M. Samardzija, and C. Grimm, “Leukemia inhibitory factor extends the lifespan of injured photoreceptors in vivo,” The Journal of Neuroscience, vol. 28, no. 51, pp. 13765–13774, 2008.
[8]
S. Bürgi, M. Samardzija, and C. Grimm, “Endogenous leukemia inhibitory factor protects photoreceptor cells against light-induced degeneration,” Molecular Vision, vol. 15, pp. 1631–1637, 2009.
[9]
M. Leibinger, A. Müller, A. Andreadaki, T. G. Hauk, M. Kirsch, and D. Fischer, “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,” The Journal of Neuroscience, vol. 29, no. 45, pp. 14334–14341, 2009.
[10]
A. Müller, T. G. Hauk, M. Leibinger, R. Marienfeld, and D. Fischer, “Exogenous CNTF stimulates axon regeneration of retinal ganglion cells partially via endogenous CNTF,” Molecular and Cellular Neuroscience, vol. 41, no. 2, pp. 233–246, 2009.
[11]
D. Fischer, “What are the principal mediators of optic nerve regeneration after inflammatory stimulation in the eye?” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 3, p. E8, 2010.
[12]
M. Leibinger, A. Müller, P. Gobrecht, H. Diekmann, A. Andreadaki, and D. Fischer, “Interleukin-6 contributes to CNS axon regeneration upon inflammatory stimulation,” Cell Death and Disease, vol. 4, article e609, 2013.
[13]
J. E. Dowling and R. L. Sidman, “Inherited retinal dystrophy in the rat,” The Journal of Cell Biology, vol. 14, pp. 73–109, 1962.
[14]
P. M. D'Cruz, D. Yasumura, J. Weir et al., “Mutation of the receptor tyrosine kinase gene Mertk in the retinal dystrophic RCS rat,” Human Molecular Genetics, vol. 9, no. 4, pp. 645–651, 2000.
[15]
A. Gal, Y. Li, D. A. Thompson et al., “Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa,” Nature Genetics, vol. 26, no. 3, pp. 270–271, 2000.
[16]
A. J. Brea-Fernández, E. Pomares, M. J. Brión et al., “Novel splice donor site mutation in MERTK gene associated with retinitis pigmentosa,” British Journal of Ophthalmology, vol. 92, no. 10, pp. 1419–1423, 2008.
[17]
B. Lorber, M. Berry, A. Logan, and D. Tonge, “Effect of lens lesion on neurite outgrowth of retinal ganglion cells in vitro,” Molecular and Cellular Neuroscience, vol. 21, no. 2, pp. 301–311, 2002.
[18]
B. Lorber, M. Berry, and A. Logan, “Different factors promote axonal regeneration of adult rat retinal ganglion cells after lens injury and intravitreal peripheral nerve grafting,” The Journal of Neuroscience Research, vol. 86, no. 4, pp. 894–903, 2008.
[19]
Y. Yin, Q. Cui, Y. Li et al., “Macrophage-derived factors stimulate optic nerve regeneration,” The Journal of Neuroscience, vol. 23, no. 6, pp. 2284–2293, 2003.
[20]
M. Berry, Z. Ahmed, B. Lorber, M. Douglas, and A. Logan, “Regeneration of axons in the visual system,” Restorative Neurology and Neuroscience, vol. 26, no. 2-3, pp. 147–174, 2008.
[21]
T. G. Hauk, A. Müller, J. Lee, R. Schwendener, and D. Fischer, “Neuroprotective and axon growth promoting effects of intraocular inflammation do not depend on oncomodulin or the presence of large numbers of activated macrophages,” Experimental Neurology, vol. 209, no. 2, pp. 469–482, 2008.
[22]
B. Lorber, M. Berry, M. R. Douglas, T. Nakazawa, and A. Logan, “Activated retinal glia promote neurite outgrowth of retinal ganglion cells via apolipoprotein E,” The Journal of Neuroscience Research, vol. 87, no. 12, pp. 2645–2652, 2009.
[23]
S. C. Kassen, R. Thummel, L. A. Campochiaro, M. J. Harding, N. A. Bennett, and D. R. Hyde, “CNTF induces photoreceptor neuroprotection and Müller glial cell proliferation through two different signaling pathways in the adult zebrafish retina,” Experimental Eye Research, vol. 88, no. 6, pp. 1051–1064, 2009.
[24]
T. L. Kent, I. V. Glybina, G. W. Abrams, and R. Iezzi, “Chronic intravitreous infusion of ciliary neurotrophic factor modulates electrical retinal stimulation thresholds in the RCS rat,” Investigative Ophthalmology and Visual Science, vol. 49, no. 1, pp. 372–379, 2008.
[25]
N. Bodeutsch, H. Siebert, C. Dermon, and S. Thanos, “Unilateral injury to the adult rat optic nerve causes multiple cellular responses in the contralateral site,” Journal of Neurobiology, vol. 38, pp. 116–128, 1999.
[26]
R. A. Bush, K. W. Hawks, and P. A. Sieving, “Preservation of inner retinal responses in the aged royal college of surgeons rat: evidence against glutamate excitotoxicity in photoreceptor degeneration,” Investigative Ophthalmology and Visual Science, vol. 36, no. 10, pp. 2054–2062, 1995.
