Fractalkine Signaling Attenuates Perivascular Clustering of Microglia and Fibrinogen Leakage during Systemic Inflammation in Mouse Models of Diabetic Retinopathy.
Fractalkine Signaling Attenuates Perivascular Clustering of Microglia and Fibrinogen Leakage during Systemic Inflammation in Mouse Models of Diabetic Retinopathy.
复制标题
分面信号传导减弱糖尿病性视网膜病变小鼠模型中全身性炎症过程中小胶质细胞和纤维蛋白原泄漏的血管周聚集。
DOI：
10.3389/fncel.2016.00303
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发表时间：
2016
影响因子：
5.3
通讯作者：
Cardona AE
中科院分区：
文献类型：
--
作者：
Mendiola AS;Garza R;Cardona SM;Mythen SA;Lira SA;Akassoglou K;Cardona AE
Fractalkine （FKN）是一种由健康神经元组成表达的趋化因子，通过与FKN受体CX3CR1相互作用向小胶质细胞发出信号。FKN和CX3CR1之间的信号转导抑制信号，改善神经炎症条件下的小胶质细胞激活和促炎细胞因子释放。本研究的目的是确定糖尿病视网膜病变（DR）期间和糖尿病患者常见的低水平内毒素血症条件下小胶质细胞激活和血管渗漏的相关机制。利用Ins2Akita菌株（Akita），一种1型糖尿病小鼠模型，我们的研究结果表明，血液蛋白纤维蛋白（原）渗漏到视网膜是慢性（4个月）而不是急性（1.5个月）高血糖的结果。相反，在急性糖尿病期间诱导内毒素介导的全身性炎症会导致视网膜纤维蛋白原沉积，这种表型在缺乏CX3CR1信号的小鼠中会加剧。Cx3cr1−/−小鼠的全身性炎症导致纤维蛋白原外溢区增殖的小胶质细胞在血管周围聚集，并诱导小胶质细胞和星形胶质细胞中IL-1β的表达。最后，我们确定了FKN/CX3CR1信号在糖尿病视网膜中的保护作用。我们发现，在糖尿病FKN- ko小鼠的玻璃体内（iv）注射重组FKN，减少了全身炎症期间视网膜纤维蛋白原沉积和血管周围小胶质细胞的聚集。这些数据表明，在全身性炎症期间，FKN/CX3CR1信号缺失导致的小胶质细胞激活失调会破坏视网膜血管的完整性。
Fractalkine (FKN) is a chemokine expressed constitutively by healthy neurons and signals to microglia upon interaction with the FKN receptor, CX3CR1. Signaling between FKN and CX3CR1 transduces inhibitory signals that ameliorate microglial activation and proinflammatory cytokine release in neuroinflammatory conditions. The aim of this study is to determine the mechanisms associated with microglial activation and vascular leakage during diabetic retinopathy (DR) and under conditions of low-level endotoxemia, common in diabetic patients. Utilizing the Ins2Akita strain (Akita), a mouse model of type 1 diabetes, our results show that leakage of the blood-protein fibrin(ogen) into the retina occurs as a result of chronic (4 months) but not acute (1.5 months) hyperglycemia. Conversely, inducing endotoxin-mediated systemic inflammation during acute diabetes resulted in fibrinogen deposition in the retina, a phenotype that was exacerbated in mice lacking CX3CR1 signaling. Systemic inflammation in Cx3cr1−/− mice led to robust perivascular clustering of proliferating microglia in areas of fibrinogen extravasation, and induced IL-1β expression in microglia and astrocytes. Lastly, we determined a protective effect of modulating FKN/CX3CR1 signaling in the diabetic retina. We show that intravitreal (iv) administration of recombinant FKN into diabetic FKN-KO mice, reduced fibrinogen deposition and perivascular clustering of microglia in the retina during systemic inflammation. These data suggest that dysregulated microglial activation via loss of FKN/CX3CR1 signaling disrupts the vascular integrity in retina during systemic inflammation.