Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts; Massachusetts Eye and Ear/Schepens Eye Research Institute, Boston Keratoprosthesis Laboratory, Harvard Medical School, Boston, Massachusetts; Disruptive Technology Laboratory, Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts.
Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts; Massachusetts Eye and Ear/Schepens Eye Research Institute, Boston Keratoprosthesis Laboratory, Harvard Medical School, Boston, Massachusetts; Disruptive Technology Laboratory, Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts.
Am J Pathol. 2018 Jul;188(7):1580-1596. doi: 10.1016/j.ajpath.2018.03.005. Epub 2018 Apr 6.
Eyes that have experienced alkali burn to the surface are excessively susceptible to subsequent severe glaucoma and retinal ganglion cell loss, despite maximal efforts to prevent or slow down the disease. Recently, we have shown, in mice and rabbits, that such retinal damage is neither mediated by the alkali itself reaching the retina nor by intraocular pressure elevation. Rather, it is caused by the up-regulation of tumor necrosis factor-α (TNF-α), which rapidly diffuses posteriorly, causing retinal ganglion cell apoptosis and CD45 cell activation. Herein, we investigated the involvement of peripheral blood monocytes and microglia in retinal damage. Using CX3CR1::CCR2 reporter mice and bone marrow chimeras, we show that peripheral CX3CR1CD45CD11bMHC-II monocytes infiltrate into the retina from the optic nerve at 24 hours after the burn and release further TNF-α. A secondary source of peripheral monocyte response originates from a rare population of patrolling myeloid CCR2 cells of the retina that differentiate into CX3CR1 macrophages within hours after the injury. As a result, CX3CR1CD45CD11b microglia become reactive at 7 days, causing further TNF-α release. Prompt TNF-α inhibition after corneal burn suppresses monocyte infiltration and microglia activation, and protects the retina. This study may prove relevant to other injuries of the central nervous system.
眼睛表面遭受碱烧伤后，极易发生后续的严重青光眼和视网膜神经节细胞丧失，尽管已尽力预防或减缓疾病进展。最近，我们在小鼠和兔模型中发现，这种视网膜损伤既不是由于碱本身到达视网膜，也不是由于眼内压升高引起的。相反，它是由肿瘤坏死因子-α（TNF-α）的上调引起的，TNF-α迅速向后扩散，导致视网膜神经节细胞凋亡和 CD45 细胞激活。在此，我们研究了外周血单核细胞和小胶质细胞在视网膜损伤中的作用。使用 CX3CR1::CCR2 报告小鼠和骨髓嵌合体，我们发现，在烧伤后 24 小时，外周 CX3CR1CD45CD11bMHC-II 单核细胞从视神经浸润到视网膜，并释放更多的 TNF-α。外周单核细胞反应的第二个来源是来自视网膜中罕见的巡弋型 CCR2 细胞的髓系细胞，这些细胞在损伤后数小时内分化为 CX3CR1 巨噬细胞。结果，CX3CR1CD45CD11b 小胶质细胞在 7 天时变得活跃，导致进一步释放 TNF-α。角膜烧伤后及时抑制 TNF-α可抑制单核细胞浸润和小胶质细胞激活，并保护视网膜。这项研究可能与中枢神经系统的其他损伤有关。
