Colony-stimulating factor 1 receptor inhibition prevents disruption of the blood-retina barrier during chronic inflammation
Colony-stimulating factor 1 receptor inhibition prevents disruption of the blood-retina barrier during chronic inflammation
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DOI：
10.1186/s12974-018-1373-4
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发表时间：
2018-12-12
影响因子：
9.3
通讯作者：
Zinkernagel, Martin S.
中科院分区：
文献类型：
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作者：
Kokona, Despina;Ebneter, Andreas;Zinkernagel, Martin S.
背景小胶质细胞相关性炎症与葡萄膜炎、糖尿病视网膜病变等多种视网膜疾病的发病机制密切相关，这些疾病与血管通透性增加有关。在这项研究中，我们探讨了全身性脂多糖（LPS）暴露的激活和视网膜小胶质细胞/macrophages.MethodsBalb/c和Cx 3cr 1（gfp/+）小鼠的增殖的影响与LPS（1 mg/kg）每天连续四天的挑战。对于小胶质细胞耗竭，在第一次LPS攻击前1周用集落刺激因子1受体（CSF-1 R）抑制剂PLX 5622处理小鼠，直到实验结束。在第一次LPS攻击后第4天和第7天，使用光学相干断层扫描和荧光素血管造影术进行视网膜的体内成像。采用流式细胞术分析、视网膜整体切片和视网膜切片研究LPS刺激后小胶质细胞和巨噬细胞的浸润和增殖。分析血液和视网膜中的细胞因子。使用非配对t检验、重复测量单因素ANOVA或普通单因素ANOVA随后进行Tukey事后分析进行数据分析。Kruskal-Wallis检验，然后由Dunn的多重比较检验用于分析非正态分布的data.ResultsRepeated LPS的挑战导致激活和增殖的视网膜小胶质细胞，单核细胞衍生的巨噬细胞浸润到视网膜，和破裂的血视网膜屏障（BRB）伴随着积累的视网膜下液。使用体内成像，我们表明，BRB的故障是高度可重复的，但短暂的。急性而非慢性全身暴露于LPS引发视网膜中炎症介质的强烈释放，对血浆的影响最小。抑制CSF-1 R的PLX 5622导致视网膜小胶质细胞的耗竭，抑制细胞因子的产生在视网膜中，并防止BRB breakdown.ConclusionsThese研究结果表明，小胶质细胞/巨噬细胞在视网膜疾病的病理学中发挥重要作用，其特征在于BRB的崩溃，抑制其激活可能是一个潜在的治疗目标，这样的视网膜病变。
BackgroundMicroglia-associated inflammation is closely related to the pathogenesis of various retinal diseases such as uveitis and diabetic retinopathy, which are associated with increased vascular permeability. In this study, we investigated the effect of systemic lipopolysaccharide (LPS) exposure to activation and proliferation of retinal microglia /macrophages.MethodsBalb/c and Cx3cr1(gfp/+) mice were challenged with LPS (1mg/kg) daily for four consecutive days. For microglia depletion, mice were treated with colony-stimulating factor 1 receptor (CSF-1R) inhibitor PLX5622 1week before the first LPS challenge and until the end of the experiment. In vivo imaging of the retina was performed on days 4 and 7 after the first LPS challenge, using optical coherence tomography and fluorescein angiography. Flow cytometry analysis, retinal whole mount, and retinal sections were used to investigate microglia and macrophage infiltration and proliferation after LPS challenge. Cytokines were analyzed in the blood as well as in the retina. Data analysis was performed using unpaired t tests, repeated measures one-way ANOVA, or ordinary one-way ANOVA followed by Tukey's post hoc analysis. Kruskal-Wallis test followed by Dunn's multiple comparison tests was used for the analysis of non-normally distributed data.ResultsRepeated LPS challenge led to activation and proliferation of retinal microglia, infiltration of monocyte-derived macrophages into the retina, and breakdown of the blood-retina barrier (BRB) accompanied by accumulation of sub-retinal fluid. Using in vivo imaging, we show that the breakdown of the BRB is highly reproducible but transitory. Acute but not chronic systemic exposure to LPS triggered a robust release of inflammatory mediators in the retina with minimal effects in the blood plasma. Inhibition of the CSF-1R by PLX5622 resulted in depletion of retinal microglia, suppression of cytokine production in the retina, and prevention of BRB breakdown.ConclusionsThese findings suggest that microglia/macrophages play an important role in the pathology of retinal disorders characterized by breakdown of the BRB, and suppression of their activation may be a potential therapeutic target for such retinopathies.