CCN1 induces hepatic ductular reaction through integrin αvβ5-mediated activation of NF-κB
CCN1 induces hepatic ductular reaction through integrin αvβ5-mediated activation of NF-κB
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DOI：
10.1172/jci79327
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发表时间：
2015-05-01
影响因子：
15.9
通讯作者：
Lau, Lester F.
中科院分区：
文献类型：
--
作者：
Kim, Ki-Hyun;Chen, Chih-Chiun;Lau, Lester F.
肝胆汁淤积性疾病的病因多种多样，可导致肝毒性和肝纤维化，并可能发展为肝硬化和肝功能衰竭。我们发现CCN1（也称为CYR61），一种抑制和解决肝纤维化的基质细胞蛋白，也介导胆管细胞增殖和导管反应，这是对胆汁淤积损伤的修复反应。在胆管细胞中，CCN1通过整合素α (v) β (5)/ α (v) β(3)激活NF-kappa B，导致Jag1表达、Jag1 /NOTCH信号传导和胆管细胞增殖。CCN1还诱导肝星状细胞中Jag1的表达，进而与肝祖细胞相互作用，促进其向胆管细胞分化。CCN1蛋白或可溶性JAG1可诱导小鼠胆管细胞增殖，这一过程可被NF-kappa B或NOTCH信号通路抑制剂阻断。表达不能结合α (v) β (5)/ α (v) β(3)的CCN1突变体的敲入小鼠在胆管反应中受损，导致胆管结扎（BDL）后大量肝坏死和死亡，而用可溶性JAG1治疗这些小鼠可恢复导管反应并减少肝坏死和死亡率。在WT小鼠中，阻断整合素α (v) β (5)/ α (v) β(3)、nf - κ B或NOTCH信号也会导致BBL后的导管反应缺陷。这些发现表明CCN1诱导胆管细胞增殖和导管反应，并确定CCN1/ α (v) β (5)/NF-kappa B/JAG1是胆道损伤修复的关键轴。
Liver cholestatic diseases, which stem from diverse etiologies, result in liver toxicity and fibrosis and may progress to cirrhosis and liver failure. We show that CCN1 (also known as CYR61), a matricellular protein that dampens and resolves liver fibrosis, also mediates cholangiocyte proliferation and ductular reaction, which are repair responses to cholestatic injury. In cholangiocytes, CCN1 activated NF-kappa B through integrin alpha(v)beta(5)/alpha(v)beta(3), leading to Jag1 expression, JAG1/NOTCH signaling, and cholangiocyte proliferation. CCN1 also induced Jag1 expression in hepatic stellate cells, whereupon they interacted with hepatic progenitor cells to promote their differentiation into cholangiocytes. Administration of CCN1 protein or soluble JAG1 induced cholangiocyte proliferation in mice, which was blocked by inhibitors of NF-kappa B or NOTCH signaling. Knock-in mice expressing a CCN1 mutant that is unable to bind alpha(v)beta(5)/alpha(v)beta(3) were impaired in ductular reaction, leading to massive hepatic necrosis and mortality after bile duct ligation (BDL), whereas treatment of these mice with soluble JAG1 rescued ductular reaction and reduced hepatic necrosis and mortality. Blockade of integrin alpha(v)beta(5)/alpha(v)beta(3), NF-kappa B, or NOTCH signaling in WT mice also resulted in defective ductular reaction after BBL. These findings demonstrate that CCN1 induces cholangiocyte proliferation and ductular reaction and identify CCN1/alpha(v)beta(5)/NF-kappa B/JAG1 as a critical axis for biliary injury repair.