Mannan-binding lectin deficiency exacerbates sterile liver injury in mice through enhancing hepatic neutrophil recruitment
Mannan-binding lectin deficiency exacerbates sterile liver injury in mice through enhancing hepatic neutrophil recruitment
复制标题
甘露聚糖结合凝集素缺乏通过增强肝脏中性粒细胞募集加剧小鼠无菌性肝损伤
DOI：
10.1002/jlb.3a0718-251r
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发表时间：
2019
影响因子：
5.5
通讯作者：
Zuo Daming
中科院分区：
文献类型：
--
作者：
Zhou Jia;Li Junru;Yu Yu;Liu Yan;Li Huifang;Liu Yunzhi;Wang Jun;Zhang Liyun;Lu Xiao;Chen Zhengliang;Zuo Daming
非感染性肝损伤，包括药物和饮食的影响，是全球肝病的主要原因。肝细胞死亡的先天炎症反应在肝损伤的转归中起着至关重要的作用。甘露聚糖结合凝集素(MBL)是天然免疫系统的一种模式识别分子，主要由肝脏产生。MBL缺乏症在人群中发生的频率很高，据报道与传染病的易感性有关。我们在这里观察到，遗传性MBL消融使小鼠对四氯化碳(CCl4)引起的无菌肝损伤高度敏感。经CCl_4染毒的−/−小鼠肝损伤加重，表现为肝细胞严重死亡，血清丙氨酸氨基转移酶和乳酸脱氢酶活性升高，炎性细胞因子的产生增加。机制研究证实，MBL缺乏导致肝巨噬细胞在CCl4刺激下产生更多趋化因子CXCL2，从而促进肝脏中性粒细胞的募集，从而促进随后的肝损伤。此外，通过注射表达MBL的肝脏特异性腺相关病毒来验证MBL对CCl_4诱导的肝损伤的保护作用，该病毒有效地改善了CCl_4处理的MBL-/-小鼠的肝损伤。我们认为MBL可作为治疗MBL缺乏症患者化学性不孕肝损伤的新方法。MBL可作为治疗MBL缺乏症患者化学性不孕性肝损伤的新方法。
Noninfectious liver injury, including the effects of drugs and diet, is a major cause of liver diseases worldwide. The innate inflammatory response to hepatocyte death plays a crucial role in the outcome of liver injury. Mannan-binding lectin (MBL) is a pattern recognition molecule of the innate immune system, which is primarily produced by liver. MBL deficiency occurs with high frequency in the population and is reported associated with predisposition to infectious diseases. We here observed that genetic MBL ablation strongly sensitizes mice to sterile liver injury induced by carbon tetrachloride (CCl4). Aggravated liver damage was shown in CCl4-administrated MBL−/−mice, as evidenced by severe hepatocyte death, elevated serum alanine aminotransferase and lactate dehydrogenase activity, and enhanced production of inflammatory cytokines. Mechanistic studies established that MBL deficiency caused increased chemokine CXCL2 production from liver macrophages upon CCl4stimulation, thereby promoting the hepatic recruitment of neutrophils and subsequent liver damage. Furthermore, MBL-mediated protection from CCl4-induced liver injury was validated by administration of an MBL-expressing liver-specific adeno-associated virus, which effectively ameliorated the hepatic damage in CCl4-treated MBL–/–mice. We propose that MBL may be exploited as a new therapeutic approach in the treatment of chemical-induced sterile liver injury in patients with MBL deficiency.MBL may be exploited as a new therapeutic approach in the treatment of chemically-induced sterile liver injury in patients with MBL deficiency.