Microglia Regulate Neuroglia Remodeling in Various Ocular and Retinal Injuries
Microglia Regulate Neuroglia Remodeling in Various Ocular and Retinal Injuries
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DOI：
10.4049/jimmunol.1800982
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发表时间：
2019-01-15
影响因子：
4.4
通讯作者：
Dohlman, Claes H.
中科院分区：
文献类型：
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作者：
Paschalis, Eleftherios I.;Lei, Fengyang;Dohlman, Claes H.
反应性小胶质细胞和浸润性外周单核细胞与视网膜和CNS的许多神经退行性疾病有关。然而，它们在视网膜变性中的具体作用仍不清楚。我们最近发现，小鼠眼损伤后浸润视网膜的外周单核细胞永久性地植入组织中，建立了促进神经变性的促炎表型。在这项研究中，我们发现小胶质细胞调节眼损伤过程中神经胶质细胞重塑的过程，它们的缺失导致视网膜中炎性标志物如IL 17 f、Tnfsf 11、Ccl 4、IL 1a、Ccr 2、IL 4、IL 5和Csf 2的显著上调，以及外周CCR2（+）CX3CR1（+）单核细胞异常植入视网膜，这与视网膜神经节细胞丢失增加、视网膜神经纤维层变薄和视网膜表面色素沉着有关。此外，我们发现其他类型的眼损伤，如穿透性角膜创伤和高眼压症也会引起类似的变化。然而，视神经挤压损伤介导的视网膜神经节细胞丢失既不会引起视网膜中的外周单核细胞反应，也不会引起色素沉着，尽管外周CX3CR1（+）和CCR2+单核细胞浸润视神经损伤部位并保持数月。我们的研究表明，小胶质细胞是外周单核细胞浸润和视网膜色素上皮细胞迁移的关键调节因子，它们的耗竭导致异常神经胶质细胞重塑，加剧神经视网膜组织损伤。这种通过神经胶质重塑的视网膜损伤机制对于治疗眼损伤（包括手术创伤）患者可能具有临床重要意义。
Reactive microglia and infiltrating peripheral monocytes have been implicated in many neurodegenerative diseases of the retina and CNS. However, their specific contribution in retinal degeneration remains unclear. We recently showed that peripheral monocytes that infiltrate the retina after ocular injury in mice become permanently engrafted into the tissue, establishing a proinflammatory phenotype that promotes neurodegeneration. In this study, we show that microglia regulate the process of neuroglia remodeling during ocular injury, and their depletion results in marked upregulation of inflammatory markers, such as Il17f, Tnfsf11, Ccl4, Il1a, Ccr2, Il4, Il5, and Csf2 in the retina, and abnormal engraftment of peripheral CCR2(+) CX3CR1(+) monocytes into the retina, which is associated with increased retinal ganglion cell loss, retinal nerve fiber layer thinning, and pigmentation onto the retinal surface. Furthermore, we show that other types of ocular injuries, such as penetrating corneal trauma and ocular hypertension also cause similar changes. However, optic nerve crush injury-mediated retinal ganglion cell loss evokes neither peripheral monocyte response in the retina nor pigmentation, although peripheral CX3CR1(+) and CCR2+ monocytes infiltrate the optic nerve injury site and remain present for months. Our study suggests that microglia are key regulators of peripheral monocyte infiltration and retinal pigment epithelium migration, and their depletion results in abnormal neuroglia remodeling that exacerbates neuroretinal tissue damage. This mechanism of retinal damage through neuroglia remodeling may be clinically important for the treatment of patients with ocular injuries, including surgical traumas.