Peptidyl arginine deiminase 4 deficiency protects against subretinal fibrosis by inhibiting Müller glial hypercitrullination.
Peptidyl arginine deiminase 4 deficiency protects against subretinal fibrosis by inhibiting Müller glial hypercitrullination.
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DOI：
10.1002/jnr.25158
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发表时间：
2023-04
影响因子：
4.2
通讯作者：
Mohan, Royce
中科院分区：
文献类型：
--
作者：
Palko, Sarah I.;Saba, Nicholas J.;Bargagna-Mohan, Paola;Mohan, Royce
关键词：
GFAPMuller glial endfeetPAD4RRID:AB_2338508RRID:AB_2534091RRID:AB_2535713RRID:AB_2535813RRID:AB_2572090RRID:AB_2762843RRID:AB_2802127RRID:AB_304558RRID:AB_306067RRID:AB_650499RRID:AB_650500RRID:AB_881875RRID:IMSR_JAX:012849RRID:IMSR_JAX:026708RRID:SCR_002798RRID:SCR_003070citrullinationretinal gliosissubretinal fibrosis
视网膜瘢痕与视力丧失仍然是一个谜，在个人先进的年龄相关性黄斑变性（AMD）。Müller神经胶质细胞被认为在视网膜变性中启动并维持瘢痕形成，因为这些神经胶质细胞参与反应性神经胶质增生并经历肥大。我们先前在模拟湿性AMD的脉络膜新生血管的小鼠激光诱导模型中显示，胶质细胞酸性蛋白（GFAP）表达（反应性胶质增生的早期标志物）随其翻译后修饰瓜氨酸沿着增加。这与瓜氨酸酶肽基精氨酸脱亚胺酶-4（PAD 4）的共表达增加有关，PAD 4也与GFAP细丝共定位。然而，Müller神经胶质中的这种高瓜氨酸血症是否会导致纤维化病理学仍然研究不足。在这里，使用受到激光损伤的雄性和雌性C57 B16小鼠，我们在一项时间研究中研究了瓜氨酸如何影响GFAP和PAD 4动力学。我们发现，Müller胶质细胞中积累的高分子量瓜氨酸化物质与GFAP和PAD 4的动态变化相对应，显示了使用免疫染色和蛋白质印迹分析从聚合细胞骨架到可溶性蛋白组分的时间再分布。在条件性神经胶质特异性PAD 4基因敲除（PAD 4cKO）小鼠激光损伤后，瓜氨酸和聚合的GFAP细丝明显减少。这些受损的PAD 4cKO视网膜在30天时显示出改善的病变愈合，以及视网膜下腔中减少的纤连蛋白沉积。综上所述，这些研究结果表明，反应性Müller神经胶质中病理性过表达的PAD 4控制GFAP丝动力学并改变其稳定性，表明慢性PAD 4驱动的高瓜氨酸血症可能是视网膜纤维化的靶点。
Retinal scarring with vision loss continues to be an enigma in individuals with advanced age-related macular degeneration (AMD). Müller glial cells are believed to initiate and perpetuate scarring in retinal degeneration as these glial cells participate in reactive gliosis and undergo hypertrophy. We previously showed in the murine laser-induced model of choroidal neovascularization that models wet-AMD that glial fibrillary acidic protein (GFAP) expression, an early marker of reactive gliosis, increases along with its posttranslational modification citrullination. This was related to increased co-expression of the citrullination enzyme peptidyl arginine deiminase-4 (PAD4), which also colocalizes to GFAP filaments. However, whether such hypercitrullination in Müller glial drives fibrotic pathology has remained understudied. Here, using male and female C57Bl6 mice subjected to laser injury, we investigated in a temporal study how citrullination impacts GFAP and PAD4 dynamics. We found that high molecular weight citrullinated species that accumulate in Müller glia corresponded with dynamic changes in GFAP and PAD4 showing their temporal redistribution from polymeric cytoskeletal to soluble protein fractions using immunostaining and western blot analysis. In conditional glial-specific PAD4 knockout (PAD4cKO) mice subjected to laser injury, there was a stark reduction of citrullination and of polymerized GFAP filaments. These injured PAD4cKO retinas showed improved lesion healing, as well as reduced fibronectin deposition in the subretinal space at 30 days. Taken together, these findings reveal that pathologically overexpressed PAD4 in reactive Müller glia governs GFAP filament dynamics and alters their stability, suggesting chronic PAD4-driven hypercitrullination may be a target for retinal fibrosis.
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