IL-17A Plays a Critical Role in the Pathogenesis of Liver Fibrosis through Hepatic Stellate Cell Activation
IL-17A Plays a Critical Role in the Pathogenesis of Liver Fibrosis through Hepatic Stellate Cell Activation
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IL-17A 通过肝星状细胞激活在肝纤维化发病机制中发挥关键作用
DOI：
10.4049/jimmunol.1203013
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发表时间：
2013-08-15
影响因子：
4.4
通讯作者：
Sun, Beicheng
中科院分区：
文献类型：
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作者：
Tan, Zhongming;Qian, Xiaofeng;Sun, Beicheng
肝纤维化是一种严重的、危及生命的临床疾病，由不同来源的未消退肝炎引起。IL-17A在炎症中起关键作用，但它与肝纤维化的关系仍然难以捉摸。我们发现，与未感染肝血管瘤的非肝纤维化患者相比，因肝硬变相关的早期肝细胞癌而行部分肝切除的乙肝病毒感染者肝纤维化中IL-17A的表达增加。在纤维化的肝脏中，IL-17A免疫反应定位于炎性浸润物。在四氯化碳诱导的IL-17RA缺陷小鼠实验性肝纤维化中，与对照组C57BL/6小鼠相比，我们观察到中性粒细胞内流减少，促炎细胞因子，肝细胞坏死，炎症和纤维化。IL-17A是由表达Th17系特异性转录因子视黄酸受体相关孤儿受体γt的中性粒细胞和T淋巴细胞产生的。此外，从幼小C57BL/6小鼠分离的肝星状细胞(HSC)对IL-17A的反应增加，IL-6、α-平滑肌肌动蛋白、胶原和转化生长因子-β基因表达增加，提示IL-17A驱动的纤维化过程。药物抑制ERK1/2或p38可显著抑制IL-17A诱导的HSC活化和胶原表达。总之，IL-17A+维甲酸受体相关的孤儿受体γt+中性粒细胞和T细胞被招募到受损的肝脏中，导致慢性纤维性肝炎。依赖IL-17A的HSC激活可能在肝纤维化中起关键作用。因此，阻断IL-17A可能会使慢性肝炎和肝纤维化患者受益。
Liver fibrosis is a severe, life-threatening clinical condition resulting from nonresolving hepatitis of different origins. IL-17A is critical in inflammation, but its relation to liver fibrosis remains elusive. We find increased IL-17A expression in fibrotic livers from HBV-infected patients undergoing partial hepatectomy because of cirrhosis-related early-stage hepatocellular carcinoma in comparison with control nonfibrotic livers from uninfected patients with hepatic hemangioma. In fibrotic livers, IL-17A immunoreactivity localizes to the inflammatory infiltrate. In experimental carbon tetrachloride–induced liver fibrosis of IL-17RA–deficient mice, we observe reduced neutrophil influx, proinflammatory cytokines, hepatocellular necrosis, inflammation, and fibrosis as compared with control C57BL/6 mice. IL-17A is produced by neutrophils and T lymphocytes expressing the Th17 lineage–specific transcription factor Retinoic acid receptor–related orphan receptor γt. Furthermore, hepatic stellate cells (HSCs) isolated from naive C57BL/6 mice respond to IL-17A with increased IL-6, α-smooth muscle actin, collagen, and TGF-β mRNA expression, suggesting an IL-17A–driven fibrotic process. Pharmacologic ERK1/2 or p38 inhibition significantly attenuated IL-17A–induced HSC activation and collagen expression. In conclusion, IL-17A+ Retinoic acid receptor–related orphan receptor γt+ neutrophils and T cells are recruited into the injured liver driving a chronic, fibrotic hepatitis. IL-17A–dependent HSC activation may be critical for liver fibrosis. Thus, blockade of IL-17A could potentially benefit patients with chronic hepatitis and liver fibrosis.