Defibrinogenation Ameliorates Retinal Microgliosis and Inflammation in A CX3CR1-Independent Manner.
Defibrinogenation Ameliorates Retinal Microgliosis and Inflammation in A CX3CR1-Independent Manner.
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除纤维蛋白原以与CX3CR1无关的方式改善视网膜小胶质细胞增多症和炎症。
DOI：
10.1177/17590914221131446
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发表时间：
2022-01
期刊：
影响因子：
4.7
通讯作者：
Cardona, Astrid E.
中科院分区：
文献类型：
--
作者：
Sarker, Borna;Cardona, Sandra M.;Church, Kaira A.;Vanegas, Difernando;Velazquez, Priscila;Rorex, Colin;Rodriguez, Derek;Mendiola, Andrew S.;Kern, Timothy S.;Domingo, Nadia D.;Stephens, Robin;Muzzio, Isabel A.;Cardona, Astrid E.
小胶质细胞介导的炎症在糖尿病视网膜病变（DR）的神经元和血管损伤中发挥着重要作用，但炎症、神经变性和血管完整性受损之间的联系机制仍不清楚。先前对糖尿病小鼠模型的研究表明，纤维蛋白原在血管周围小胶质细胞簇包围的血管病变处积聚。本研究的目的是评估糖尿病动物模型中神经胶质增生和血管畸变的病理特征是否与糖尿病人类视网膜中的一致，并评估去纤维蛋白原剂 ancrod 对二次炎症糖尿病小鼠模型视网膜病理和视力的影响。通过定量 PCR 评估死后人眼的视网膜和炎症基因表达。使用神经胶质增生、血管完整性和纤维蛋白原沉积的标记物对人和小鼠视网膜进行免疫组织化学分析。在糖尿病人眼中发现了具有小胶质细胞增生和微动脉瘤的炎症微环境。在糖尿病小鼠视网膜中也观察到小胶质细胞活化、纤维蛋白原沉积和轴突丢失。 Ancrod 治疗与患病视网膜组织中小胶质细胞增生的减少、纤维蛋白原沉积的减少以及促炎细胞因子水平的降低相关。总之，这些数据表明纤维蛋白原有助于糖尿病视网膜中小胶质细胞介导的炎症。由于无论CX3CR1基因型如何，糖尿病小鼠都会出现视网膜小胶质细胞增生、血管病理学和视力缺陷，因此我们的结果表明，去纤维蛋白原可以抑制全身神经炎症和血管损伤，从而改善糖尿病早期的视力。糖尿病人和小鼠视网膜显示出明显的小胶质细胞形态激活和与炎症相关的血管异常。使用 ancrod 进行药理学纤维蛋白原消耗，可以抑制小胶质细胞形态的改变，解决纤维蛋白原积累问题，挽救轴突完整性，并减少糖尿病小鼠视网膜的炎症。
Microglia-mediated inflammation plays a significant role in neuronal and vascular damage in diabetic retinopathy (DR), but the mechanism linking inflammation, neurodegeneration, and impaired vascular integrity is still unclear. Previous studies from diabetic mouse models showed accumulation of fibrinogen at vessel lesions surrounded by perivascular microglial clusters. The purpose of this study was to evaluate whether the pathological hallmarks of gliosis and vascular aberrations characterized in diabetic animal models are consistent with those in diabetic human retinas, and to assess the effects of the defibrinogenating agent ancrod in retinal pathology and visual acuity in a two-hit inflammatory diabetic mouse model. Post-mortem human eyes were assessed for retinal and inflammatory gene expression by quantitative PCR. Immunohistochemical analyses in human and murine retinas were performed using markers of gliosis, vascular integrity, and fibrinogen deposition. An inflammatory microenvironment, with microgliosis and microaneurysms, was found in the diabetic human eye. Microglial activation, fibrinogen deposition, and axonal loss were also observed in the diabetic murine retina. Ancrod treatment correlated with reduced microgliosis, less fibrinogen deposition, and reduced pro-inflammatory cytokine levels in diseased retinal tissues. Together, these data suggest that fibrinogen contributes to microglia-mediated inflammation in the diabetic retina. Since retinal microgliosis, vascular pathology, and vision deficits manifest in diabetic mice irrespective of CX3CR1 genotype, our results indicate that defibrinogenation can dampen systemic neuroinflammation and vascular insults, thereby improving vision at early stages of diabetes. Diabetic human and murine retinas revealed pronounced microglial morphological activation and vascular abnormalities associated with inflammation. Pharmacological fibrinogen depletion using ancrod dampened microglial morphology alterations, resolved fibrinogen accumulation, rescued axonal integrity, and reduced inflammation in the diabetic murine retina.
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影响因子：
--
作者：
Kern, Timothy S.
通讯作者：
Kern, Timothy S.
影响因子：
16.6
作者：
通讯作者：
--
影响因子：
8.2
作者：
Burgos, R;Simo, R;Carrascosa, A
通讯作者：
Carrascosa, A
影响因子：
4.7
作者：
Cardona SM;Mendiola AS;Yang YC;Adkins SL;Torres V;Cardona AE
通讯作者：
Cardona AE
影响因子：
5.2
作者：
Fink MP
通讯作者：
Fink MP