Lack of IL-17 signaling decreases liver fibrosis in murine schistosomiasis japonica
Lack of IL-17 signaling decreases liver fibrosis in murine schistosomiasis japonica
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IL-17信号传导缺失可降低小鼠日本血吸虫病的肝纤维化
DOI：
10.1093/intimm/dxv017
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发表时间：
2015
影响因子：
4.4
通讯作者：
Shen Jijia
中科院分区：
文献类型：
--
作者：
Zhang Yuxia;Huang Dake;Gao Wenda;Yan Jun;Zhou Wanling;Hou Xin;Liu Miao;Ren Cuiping;Wang Siying;Shen Jijia
越来越多的证据已经确定了IL-17A在器官纤维化中的促纤维化特性。然而，IL-17A信号在日本血吸虫感染肝纤维化中的作用尚不清楚。在这项研究中，我们研究了野生型（WT）和IL-17RA−/−小鼠的肝纤维化。japonicuminfection。采用RT-PCR检测肝脏IL-17A、IL-17C、IL-17E （IL-25）、IL-17F、IL-17RA、IL-17RB和IL-17RC转录物水平。用流式细胞术和共聚焦显微镜对肉芽肿细胞中IL-17A+细胞进行分析。肝切片进行IL-17R免疫染色。Van Gieson染色法检测胶原沉积。纤维化肝组织中IL-17A、IL-17C、IL-17E、IL-17F、IL-17RA和IL-17RC mRNA水平显著升高。在肉芽肿细胞中，CD3+和CD3−淋巴细胞、中性粒细胞和巨噬细胞表达IL-17A。与WT相比，IL-17RA−/−小鼠表现出肉芽肿性炎症减轻、肝纤维化、肝功能改善和高生存率。同时，IL-17RA−/−小鼠α-平滑肌肌动蛋白染色和纤维化基因（转化生长因子β、IL-13和胶原- i）以及il - 17a诱导的促炎介质（IL-1β、IL-6、肿瘤坏死因子α、CXCL1和CXCL2）和参与纤维化的蛋白酶（MMP3和TIMP1）的表达均显著降低。此外，IL-17RA−/−小鼠的Th2细胞因子IL-4和IL-17E （IL-25）也降低。提示IL-17A信号参与了小鼠血吸虫病肝纤维化的发病机制。这种作用可能是通过激活肝星状细胞和刺激促炎细胞因子和趋化因子的释放而诱导的。此外，IL-17A信号也增强了Th2应答。我们的数据表明，IL-17A可能作为抗纤维化治疗的一个有希望的靶点。
Accumulating evidence has identified the profibrogenic properties of IL-17A in organ fibrosis. However, the role of IL-17A signal in liver fibrosis induced bySchistosoma japonicuminfection remains unclear. In this study, we investigated liver fibrosis in wild-type (WT) and IL-17RA−/−mice uponS. japonicuminfection. Hepatic IL-17A, IL-17C, IL-17E (IL-25), IL-17F, IL-17RA, IL-17RB and IL-17RC transcript levels were determined by RT-PCR. IL-17A+cells were analyzed by flow cytometry and confocal microscopy among granuloma cells. Immunostaining of IL-17R was performed on liver sections. Collagen deposition was assessed by Van Gieson’s staining. IL-17A, IL-17C, IL-17E, IL-17F, IL-17RA and IL-17RC mRNA levels were dramatically increased in fibrotic livers. Among granuloma cells, CD3+and CD3−lymphocytes, neutrophils and macrophages were found to express IL-17A. Compared to WT, IL-17RA−/−mice displayed attenuated granulomatous inflammation, liver fibrosis, improved liver function and high survival. Meanwhile, α-smooth muscle actin staining and the expression of fibrogenic genes (transforming growth factor β, IL-13 and collagen-I) as well as IL-17A–induced proinflammatory mediators (IL-1β, IL-6, tumor necrosis factor α, CXCL1 and CXCL2) and proteinases (MMP3 and TIMP1) involved in fibrosis were markedly reduced in IL-17RA−/−mice. In addition, Th2 cytokines IL-4 and IL-17E (IL-25) were also decreased in IL-17RA−/−mice. These results indicated that IL-17A signal contributes to the pathogenesis of liver fibrosis in murine schistosomiasis. This effect was induced possibly by activating hepatic stellate cells and stimulating the release of proinflammatory cytokines and chemokines. Furthermore, the Th2 response was also enhanced by IL-17A signals. Our data demonstrate that IL-17A may serve as a promising target for antifibrotic therapy.