Netrin-1 regulates the inflammatory response of neutrophils and macrophages, and suppresses ischemic acute kidney injury by inhibiting COX-2-mediated PGE2 production.
Netrin-1 regulates the inflammatory response of neutrophils and macrophages, and suppresses ischemic acute kidney injury by inhibiting COX-2-mediated PGE2 production.
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DOI：
10.1038/ki.2012.423
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发表时间：
2013-06
影响因子：
19.6
通讯作者：
中科院分区：
文献类型：
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Netrin-1调节炎症，但其发生机制尚不清楚。在这里，我们探讨netrin-1在调节前列腺素类代谢产物PGE 2的中性粒细胞在体外和体内疾病模型的生产中的作用。野生型和RAG-1基因敲除小鼠的缺血再灌注诱导了严重的肾损伤，这与中性粒细胞浸润和浸润白细胞中考克斯-2表达的大量增加有关。给药netrin-1抑制考克斯-2表达、PGE 2和血栓素生成以及中性粒细胞浸润到肾脏。这与减少细胞凋亡、炎性细胞因子和趋化因子表达以及改善肾功能有关。用PGE 2受体EP 4激动剂治疗增强了中性粒细胞浸润和肾损伤，这不受netrin-1抑制。与体内数据一致，netrin-1在体外通过抑制考克斯-2表达抑制了巨噬细胞中LPS和IFNγ诱导的炎性细胞因子产生以及中性粒细胞中IL-17诱导的IFNγ产生。此外，netrin-1通过调节NFκB的活化，在转录水平上调节考克斯-2的表达。因此，netrin-1通过抑制考克斯-2介导的PGE 2产生来调节嗜中性粒细胞和巨噬细胞的炎症反应。这可能是一种治疗许多炎症性免疫疾病的潜在药物。
Netrin-1 regulates inflammation but the mechanism by which this occurs is unknown. Here we explore the role of netrin-1 in regulating the production of the prostanoid metabolite PGE2 from neutrophils in in vitro and in vivo disease models. Ischemia reperfusion in wild-type and RAG-1 knockout mice induced severe kidney injury that was associated with a large increase in neutrophil infiltration and COX-2 expression in the infiltrating leukocytes. Administration of netrin-1 suppressed COX-2 expression, PGE2 and thromboxane production, and neutrophil infiltration into the kidney. This was associated with reduced apoptosis, inflammatory cytokine and chemokine expression, and improved kidney function. Treatment with the PGE2 receptor EP4 agonist enhanced neutrophil infiltration and renal injury which was not inhibited by netrin-1. Consistent with in vivo data, both LPS and IFNγ-induced inflammatory cytokine production in macrophages and IL-17-induced IFNγ production in neutrophils were suppressed by netrin-1 in vitro by suppression of COX-2 expression. Moreover, netrin-1 regulates COX-2 expression at the transcriptional level through the regulation of NFκB activation. Thus, netrin-1 regulates the inflammatory response of neutrophils and macrophages through suppression of COX-2 mediated PGE2 production. This could be a potential drug for treating many inflammatory immune disorders.
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DOI：
10.1159/000142934
发表时间：
2008
期刊：
Nephron. Experimental nephrology
影响因子：
--
作者：
Kinsey GR;Li L;Okusa MD
通讯作者：
Okusa MD
影响因子：
6.1
作者：
Jo, SK;Sung, SA;Kim, HK
通讯作者：
Kim, HK
影响因子：
4.4
作者：
Lukiw, WJ;Ottlecz, A;Bazan, NG
通讯作者：
Bazan, NG
影响因子：
15.9
作者：
Leemans, JC;Stokman, G;Florquin, S
通讯作者：
Florquin, S
影响因子：
19.6
作者：
Bonventre, JV;Zuk, A
通讯作者：
Zuk, A