An endoplasmic reticulum protein, Nogo-B, facilitates alcoholic liver disease through regulation of kupffer cell polarization.
An endoplasmic reticulum protein, Nogo-B, facilitates alcoholic liver disease through regulation of kupffer cell polarization.
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DOI：
10.1002/hep.29051
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发表时间：
2017-05
期刊：
影响因子：
--
通讯作者：
Iwakiri Y
中科院分区：
文献类型：
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作者：
Park JK;Shao M;Kim MY;Baik SK;Cho MY;Utsumi T;Satoh A;Ouyang X;Chung C;Iwakiri Y
Nogo-B （Reticulon 4B）是一种调节内质网结构和功能的内质网驻留蛋白。由于已知内质网应激可诱导M2巨噬细胞极化，我们研究了Nogo-B是否调节Kupffer细胞的M1/M2极化并改变酒精性肝病（ALD）的发病机制。评估ALD患者肝脏标本（NCT01875211）中M1和M2表型与Nogo-B表达和疾病严重程度的关系。野生型（WT）和Nogo-B敲除型（KO）小鼠肝脏标本分别饲喂对照组和Lieber-DeCarli乙醇液体饲料（5%乙醇）6周，分析肝损伤和脂肪变性。从WT和Nogo-B小鼠中分离Kupffer细胞，评估M1和M2的激活情况。Nogo-B阳性Kupffer细胞与ALD患者病情严重程度呈正相关（n=30, r=0.66, p=0.048）。此外，在这些患者中，Nogo-B阳性Kupffer细胞与M1激活（iNOS）相关（r=0.50, p=0.05），与M2状态标志物（CD163）负相关（r= - 0.48, p=0.07）。与Nogo-B KO小鼠相比，WT小鼠对慢性乙醇喂养的肝损伤显著增加（p<0.05），肝脏甘油三酯水平显著升高（p<0.01）。Kupffer细胞中的Nogo-B促进了M1极化，而缺乏Nogo-B则增加了Kupffer细胞的内质网应激和M2极化。Nogo-B允许库普弗细胞M1极化，从而加重人和小鼠ALD的肝损伤。Kupffer细胞中的Nogo-B可能是治疗ALD的新靶点。
Nogo-B (Reticulon 4B) is an endoplasmic reticulum (ER) resident protein that regulates ER structure and function. Since ER stress is known to induce M2 macrophage polarization, we examined whether Nogo-B regulates M1/M2 polarization of Kupffer cells and alters the pathogenesis of alcoholic liver disease (ALD). M1 and M2 phenotypes were assessed in relation to Nogo-B expression and disease severity in liver specimens from ALD patients (NCT01875211). Liver specimens from wild-type (WT) and Nogo-B knockout (KO) mice fed control or Lieber-DeCarli ethanol liquid diet (5% ethanol) for 6 weeks were analyzed for liver injury and steatosis. Kupffer cells isolated from WT and Nogo-B KO mice were assessed for M1 and M2 activation. A significant positive correlation was observed between Nogo-B positive Kupffer cells and disease severity in ALD patients (n=30, r=0.66, p=0.048). Further, Nogo-B positive Kupffer cells correlated with M1 activation (iNOS) (r=0.50, p=0.05) and negatively with markers of M2 status (CD163) (r=−0.48, p=0.07) in these patients. WT mice exhibited significantly increased liver injury (p<0.05) and higher hepatic triglyceride levels (p<0.01), compared to Nogo-B KO mice in response to chronic ethanol feeding. Nogo-B in Kupffer cells promoted M1 polarization, whereas absence of Nogo-B increased ER stress and M2 polarization in Kupffer cells. Nogo-B is permissive for M1 polarization of Kupffer cells, thereby accentuating liver injury in ALD in humans and mice. Nogo-B in Kupffer cells may represent a new therapeutic target for ALD.