Zhang Shuai, Zhang Shanshan, Gong Wenqing, Zhu Guopei, Wang Songtao, Wang Yalin, Halim Michael, Wang Kaidi, Zhou Guomin, Liu Qiong
Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Shanghai, China.
Front Neurosci. 2018 Dec 3;12:890. doi: 10.3389/fnins.2018.00890. eCollection 2018.
During the pathogenesis of retinitis pigmentosa (RP), the roles of retinal microglial cells after activation have not been fully elucidated. Herein, experimental RP was induced in Sprague Dawley rats by intraperitoneal injection of -methyl--nitrosourea (MNU) at 50 mg/kg, and the effects of MNU on the retinas were evaluated, respectively, by retinal histology and electroretinography recordings at serial time points. Time-dependent and gradual loss of photoreceptor cells, disrupted arrangement of the outer nuclear layer (ONL), and significant reductions in both a-wave and b-wave amplitudes were observed. Morphology changes were observed in retinal microglial cells; meanwhile, with time, the number of Iba1-positive microglia and their infiltration into the ONL gradually increased. Furthermore, physical interaction of microglial-Müller cell processes following microglial activation was observed after MNU injection. In addition, Müller cells increased CX3CL1 secretion, enhanced microglial cell migration, and upregulated the CX3CR1 expression of the latter. Our observations implied that, during the pathogenesis of RP by MNU, microglial cells exhibit a prominent morphology change and Müller cells can induce activated microglia infiltration by increasing secretion of the chemotaxis factor, CX3CL1, and promoting the migration of retinal microglial cells. This novel finding highlights a potential therapeutic target aimed at regulating the microglial response.
在视网膜色素变性（RP）的发病机制中，视网膜小胶质细胞激活后的作用尚未完全阐明。在此，通过腹腔注射50mg/kg的甲基亚硝基脲（MNU）在Sprague Dawley大鼠中诱导实验性RP，并在连续时间点分别通过视网膜组织学和视网膜电图记录评估MNU对视网膜的影响。观察到光感受器细胞随时间逐渐丧失、外核层（ONL）排列紊乱以及a波和b波振幅显著降低。视网膜小胶质细胞出现形态学变化；同时，随着时间的推移，Iba1阳性小胶质细胞的数量及其向ONL的浸润逐渐增加。此外，在注射MNU后观察到小胶质细胞激活后小胶质细胞与Müller细胞突起之间的物理相互作用。另外，Müller细胞增加CX3CL1分泌，增强小胶质细胞迁移，并上调后者的CX3CR1表达。我们的观察结果表明，在MNU诱导的RP发病机制中，小胶质细胞表现出明显的形态学变化，并且Müller细胞可以通过增加趋化因子CX3CL1的分泌和促进视网膜小胶质细胞的迁移来诱导活化的小胶质细胞浸润。这一新发现突出了一个旨在调节小胶质细胞反应的潜在治疗靶点。
