Neuroscience Graduate Program, University of Michigan, Ann Arbor, Michigan.
Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan.
Glia. 2020 Jul;68(7):1445-1465. doi: 10.1002/glia.23792. Epub 2020 Feb 8.
Brain injury activates complex inflammatory signals in dying neurons, surviving neurons, and glia. Here, we establish that inflammation regulates the regeneration of photoreceptors in the zebrafish retina and determine the cellular expression and function of the inflammatory protease, matrix metalloproteinase 9 (Mmp-9), during this regenerative neurogenesis. Following photoreceptor ablation, anti-inflammatory treatment suppresses the number of injury-induced progenitors and regenerated photoreceptors. Upon photoreceptor injury, mmp-9 is induced in Müller glia and Müller glia-derived photoreceptor progenitors. Deleting mmp-9 results in over production of injury-induced progenitors and regenerated photoreceptors, but over time the absence of Mmp-9 compromises the survival of the regenerated cones. At all time-points studied, the levels of tnf-α are significantly elevated in mutant retinas. Anti-inflammatory treatment in mutants rescues the defects in cone survival. These data provide a link between injury-induced inflammation in the vertebrate CNS, Mmp-9 function during neuronal regeneration and the requirement of Mmp-9 for the survival of regenerated cones.
脑损伤会在死亡神经元、存活神经元和神经胶质细胞中激活复杂的炎症信号。在这里，我们证实炎症会调节斑马鱼视网膜中光感受器的再生，并确定在这种再生神经发生过程中炎症蛋白酶基质金属蛋白酶 9（Mmp-9）的细胞表达和功能。在光感受器消融后，抗炎治疗会抑制损伤诱导的祖细胞和再生光感受器的数量。在光感受器损伤后，Mmp-9 在 Müller 胶质细胞和 Müller 胶质细胞衍生的光感受器祖细胞中被诱导。删除 mmp-9 会导致损伤诱导的祖细胞和再生光感受器过度产生，但随着时间的推移，Mmp-9 的缺失会损害再生锥体的存活。在所有研究的时间点，突变体视网膜中的 tnf-α 水平显著升高。在突变体中进行抗炎治疗可挽救锥体存活的缺陷。这些数据为脊椎动物中枢神经系统中损伤诱导的炎症、Mmp-9 在神经元再生过程中的功能以及 Mmp-9 对再生锥体存活的要求之间提供了联系。
