Pentraxin-2 suppresses c-Jun/AP-1 signaling to inhibit progressive fibrotic disease
Pentraxin-2 suppresses c-Jun/AP-1 signaling to inhibit progressive fibrotic disease
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DOI：
10.1172/jci.insight.87446
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发表时间：
2016-12-08
期刊：
影响因子：
8
通讯作者：
Duffield, Jeremy S.
中科院分区：
文献类型：
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作者：
Nakagawa, Naoki;Barron, Luke;Duffield, Jeremy S.
pentaxin -2 (PTX-2)，也被称为血清淀粉样蛋白P组分（SAP/APCS），是一种组成性，抗炎，先天免疫血浆蛋白，其循环水平在慢性人类纤维化疾病中降低。本研究表明，重组人PTX-2 （rhPTX-2）可以延缓患有Alport综合征的Col4a3突变小鼠慢性肾脏疾病的进展，降低肾衰竭的血液标志物，延长20%的寿命，并改善疾病的组织学体征。外源性递送的rhPTX-2在巨噬细胞中检测到，但也在小管上皮细胞中检测到，在那里它抵消了巨噬细胞的激活，并对上皮具有细胞保护作用。对rhPTX-2调控基因的计算分析发现，转录调控因子c-Jun及其激活蛋白1 （activator protein-1, AP-1）结合伙伴是rhPTX-2功能的中心靶点。因此，PTX-2减弱c-Jun和AP-1活性，并降低单核细胞和上皮中AP-1依赖性炎症基因的表达。因此，我们的研究确定了rhPTX-2作为慢性肾脏纤维化疾病的潜在治疗方法和病理性c-Jun信号的重要抑制剂。
Pentraxin-2 (PTX-2), also known as serum amyloid P component (SAP/APCS), is a constitutive, antiinflammatory, innate immune plasma protein whose circulating level is decreased in chronic human fibrotic diseases. Here we show that recombinant human PTX-2 (rhPTX-2) retards progression of chronic kidney disease in Col4a3 mutant mice with Alport syndrome, reducing blood markers of kidney failure, enhancing lifespan by 20%, and improving histological signs of disease. Exogenously delivered rhPTX-2 was detected in macrophages but also in tubular epithelial cells, where it counteracted macrophage activation and was cytoprotective for the epithelium. Computational analysis of genes regulated by rhPTX-2 identified the transcriptional regulator c-Jun along with its activator protein-1 (AP-1) binding partners as a central target for the function of rhPTX-2. Accordingly, PTX-2 attenuates c-Jun and AP-1 activity, and reduces expression of AP-1-dependent inflammatory genes in both monocytes and epithelium. Our studies therefore identify rhPTX-2 as a potential therapy for chronic fibrotic disease of the kidney and an important inhibitor of pathological c-Jun signaling in this setting.