Leibinger Marco, Müller Adrienne, Andreadaki Anastasia, Hauk Thomas G, Kirsch Matthias, Fischer Dietmar
Department of Experimental Neurology, University of Ulm, 89081 Ulm, Germany.
J Neurosci. 2009 Nov 11;29(45):14334-41. doi: 10.1523/JNEUROSCI.2770-09.2009.
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.
视神经损伤后，视网膜神经节细胞（RGCs）通常无法在视神经中再生轴突并发生凋亡。然而，晶状体损伤（LI）或玻璃体腔内注射酵母聚糖可使RGCs转变为活跃的再生状态，使这些神经元能够在轴突切断后存活并将轴突再生至受损的视神经中。已有多种因素被提出介导LI的有益作用。在此，我们使用野生型和CNTF缺陷型小鼠研究了胶质细胞源性睫状神经营养因子（CNTF）对LI介导的再生和神经保护的作用。在野生型小鼠中，视网膜星形胶质细胞中CNTF表达强烈上调，RGCs中的JAK/STAT3信号通路被激活，且LI后RGCs转变为活跃的再生状态。有趣的是，LI后视网膜白血病抑制因子（LIF）表达与CNTF表达相关。在CNTF缺陷型小鼠中，尽管观察到CNTF缺陷型小鼠中LIF表达有代偿性上调，但LI的神经保护和促进轴突生长的作用与野生型动物相比仍显著降低。在CNTF/LIF双敲除小鼠中，LI以及酵母聚糖的积极作用完全消失，而LI诱导的胶质细胞和巨噬细胞激活并未受损。在培养中，CNTF和LIF显著刺激成熟RGCs的神经突生长。这些数据证实了CNTF在直接介导眼部炎症刺激的神经保护和轴突再生作用中的关键作用，并确定LIF为另一个促成因素。
