Arginase activity mediates retinal inflammation in endotoxin-induced uveitis.
Arginase activity mediates retinal inflammation in endotoxin-induced uveitis.
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DOI：
10.2353/ajpath.2009.081115
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发表时间：
2009-08
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通讯作者：
Wenbo Zhang;B. Baban;M. Rojas;Sohrab Tofigh;S. K. Virmani;C. Patel;M. Behzadian;Maritza J. Romero-Maritza-J.-Rome
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作者：
Wenbo Zhang;B. Baban;M. Rojas;Sohrab Tofigh;S. K. Virmani;C. Patel;M. Behzadian;Maritza J. Romero-Maritza-J.-Rome
据报道，精氨酸酶可降低心血管疾病中一氧化氮的生物利用度。然而，其在视网膜病变中的具体作用尚未研究。在这项研究中，我们评估了内毒素诱导的葡萄膜炎的小鼠模型中的作用，由脂多糖（LPS）治疗诱导的。视网膜中的精氨酸酶表达和活性的测量显示，精氨酸酶活性显著增加，这与精氨酸酶（Arg）1的mRNA和蛋白质水平的增加有关，但与Arg 2无关。免疫荧光和流式细胞术证实了Arg1的这种增加，Arg1定位于神经胶质细胞和小胶质细胞。LPS处理的Muller细胞和小胶质细胞中Arg1的表达和活性也增加。为了测试精氨酸酶是否在视网膜炎症的发展中起作用，在缺乏Arg1基因的一个拷贝和Arg2基因的两个拷贝的小鼠中或在用选择性精氨酸酶抑制剂治疗的小鼠中进行实验。这些研究表明，LPS诱导的炎性蛋白产生、白细胞停滞、视网膜损伤、前葡萄膜炎体征和一氧化氮合酶解偶联的增加可通过敲低或抑制NOS来阻断。此外，LPS诱导的Arg1表达的增加通过阻断NADPH氧化酶而被废除。总之，这些研究表明，内毒素诱导的葡萄膜炎中LPS诱导的视网膜炎症是由NADPH氧化酶依赖性的NADPH氧化酶活性增加介导的。
Arginase has been reported to reduce nitric oxide bioavailability in cardiovascular disease. However, its specific role in retinopathy has not been studied. In this study, we assessed the role of arginase in a mouse model of endotoxin-induced uveitis induced by lipopolysaccharide (LPS) treatment. Measurement of arginase expression and activity in the retina revealed a significant increase in arginase activity that was associated with increases in both mRNA and protein levels of arginase (Arg)1 but not Arg2. Immunofluorescence and flow cytometry confirmed this increase in Arg1, which was localized to glia and microglia. Arg1 expression and activity were also increased in cultured Muller cells and microglia treated with LPS. To test whether arginase has a role in the development of retinal inflammation, experiments were performed in mice deficient in one copy of the Arg1 gene and both copies of the Arg2 gene or in mice treated with a selective arginase inhibitor. These studies showed that LPS-induced increases in inflammatory protein production, leukostasis, retinal damage, signs of anterior uveitis, and uncoupling of nitric oxide synthase were blocked by either knockdown or inhibition of arginase. Furthermore, the LPS-induced increase in Arg1 expression was abrogated by blocking NADPH oxidase. In conclusion, these studies suggest that LPS-induced retinal inflammation in endotoxin-induced uveitis is mediated by NADPH oxidase-dependent increases in arginase activity.