Department of Ophthalmology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.
Department for BioMedical Research, University of Bern, Bern, Switzerland.
Glia. 2020 Mar;68(3):574-588. doi: 10.1002/glia.23739. Epub 2019 Oct 25.
The role of microglia in retinal inflammation is still ambiguous. Branch retinal vein occlusion initiates an inflammatory response whereby resident microglia cells are activated. They trigger infiltration of neutrophils that exacerbate blood-retina barrier damage, regulate postischemic inflammation and irreversible loss of neuroretina. Suppression of microglia-mediated inflammation might bear potential for mitigating functional impairment after retinal vein occlusion (RVO). To test this hypothesis, we depleted microglia by PLX5622 (a selective tyrosine kinase inhibitor that targets the colony-stimulating factor-1 receptor) in fractalkine receptor reporter mice (Cx3cr1 ) subjected to various regimens of PLX5622 treatment and experimental RVO. Effectiveness of microglia suppression and retinal outcomes including retinal thickness as well as ganglion cell survival were compared to a control group of mice with experimental vein occlusion only. PLX5622 caused dramatic suppression of microglia. Despite vein occlusion, reappearance of green fluorescent protein positive cells was strongly impeded with continuous PLX5622 treatment and significantly delayed after its cessation. In depleted mice, retinal proinflammatory cytokine signaling was diminished and retinal ganglion cell survival improved by almost 50% compared to nondepleted animals 3 weeks after vein occlusion. Optical coherence tomography suggested delayed retinal degeneration in depleted mice. In summary, findings indicate that suppression of cells bearing the colony-stimulating factor-1 receptor, mainly microglia and monocytes, mitigates ischemic damage and salvages retinal ganglion cells. Blood-retina barrier breakdown seems central in the disease mechanism, and complex interactions between different cell types composing the blood-retina barrier as well as sustained hypoxia might explain why the protective effect was only partial.
小胶质细胞在视网膜炎症中的作用仍不明确。分支性视网膜静脉阻塞会引发炎症反应，使固有小胶质细胞被激活。它们触发中性粒细胞的浸润，加剧血视网膜屏障的损伤，调节缺血后的炎症和神经视网膜的不可逆转损失。抑制小胶质细胞介导的炎症可能有助于减轻视网膜静脉阻塞（RVO）后的功能障碍。为了验证这一假说，我们使用 PLX5622（一种针对集落刺激因子-1 受体的选择性酪氨酸激酶抑制剂）在 fractalkine 受体报告小鼠（Cx3cr1 ）中耗竭小胶质细胞，这些小鼠接受了不同方案的 PLX5622 治疗和实验性 RVO。与仅接受实验性静脉阻塞的对照组小鼠相比，我们比较了小胶质细胞抑制的效果以及视网膜结果，包括视网膜厚度和节细胞存活。PLX5622 导致小胶质细胞的显著抑制。尽管发生了静脉阻塞，但在持续给予 PLX5622 治疗的情况下，绿色荧光蛋白阳性细胞的再次出现受到强烈阻碍，并且在停止治疗后显著延迟。在耗竭的小鼠中，与未耗竭的动物相比，视网膜促炎细胞因子信号减弱，视网膜节细胞存活提高了近 50%，静脉阻塞后 3 周。光学相干断层扫描提示耗竭小鼠的视网膜变性延迟。总之，这些发现表明，抑制携带集落刺激因子-1 受体的细胞，主要是小胶质细胞和单核细胞，可以减轻缺血性损伤并挽救视网膜节细胞。血视网膜屏障的破坏似乎是疾病机制的核心，不同细胞类型之间的复杂相互作用以及持续的缺氧可能解释了为什么保护作用只是部分的。
