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长期营养不良损害TREM2依赖性胞葬作用来促进慢性肝脏炎症和NASH的发展
2022-12-15 15:58
来源：小柯机器人

美国德克萨斯大学Zhenyu Zhong等研究人员合作发现，长期营养不良损害TREM2依赖性胞葬作用来促进慢性肝脏炎症和NASH的发展。这一研究成果于2022年12月14日在线发表在国际学术期刊《免疫》上。

研究人员表明，由肝细胞衍生的鞘氨醇-1-磷酸诱导的巨噬细胞吞噬受体TREM2是脂质细胞凋亡的肝细胞胞葬作用所需的，从而维持肝脏免疫平衡。然而，长期的营养不良导致肝脏产生促炎症细胞因子TNF和IL-1β，通过ADAM17依赖性的蛋白水解诱导TREM2的脱落。TREM2的缺失导致垂死肝细胞的异常积累，从而进一步增强了促炎症细胞因子的产生。这最终催生了一个恶性循环，使得慢性炎症推动简单的脂肪变性过渡到NASH。因此，巨噬细胞吞噬功能受损是以前没有认识到的一个关键致病事件，使肥胖症的慢性肝脏炎症得以发生。阻断TREM2切割来恢复吞噬功能可能是治疗非酒精性脂肪性肝炎（NASH）的一个有效策略。
 
据介绍，肥胖引起的慢性肝脏炎症是NASH的一个标志，这是非酒精性脂肪性肝病的一种侵略性形式。然而，目前仍不清楚这样一种低级但持续的炎症是如何在肝脏中持续存在的。
 
附：英文原文

Title: Prolonged hypernutrition impairs TREM2-dependent efferocytosis to license chronic liver inflammation and NASH development

Author: Xiaochen Wang, Qifeng He, Chuanli Zhou, Yueyuan Xu, Danhui Liu, Naoto Fujiwara, Naoto Kubota, Arielle Click, Polly Henderson, Janiece Vancil, Cesia Ammi Marquez, Ganesh Gunasekaran, Myron E. Schwartz, Parissa Tabrizian, Umut Sarpel, Maria Isabel Fiel, Yarui Diao, Beicheng Sun, Yujin Hoshida, Shuang Liang, Zhenyu Zhong

Issue&Volume: 2022-12-14

Abstract: Obesity-induced chronic liver inflammation is a hallmark of nonalcoholic steatohepatitis(NASH)—an aggressive form of nonalcoholic fatty liver disease. However, it remainsunclear how such a low-grade, yet persistent, inflammation is sustained in the liver.Here, we show that the macrophage phagocytic receptor TREM2, induced by hepatocyte-derivedsphingosine-1-phosphate, was required for efferocytosis of lipid-laden apoptotic hepatocytesand thereby maintained liver immune homeostasis. However, prolonged hypernutritionled to the production of proinflammatory cytokines TNF and IL-1β in the liver to induceTREM2 shedding through ADAM17-dependent proteolytic cleavage. Loss of TREM2 resultedin aberrant accumulation of dying hepatocytes, thereby further augmenting proinflammatorycytokine production. This ultimately precipitated a vicious cycle that licensed chronicinflammation to drive simple steatosis transition to NASH. Therefore, impaired macrophageefferocytosis is a previously unrecognized key pathogenic event that enables chronicliver inflammation in obesity. Blocking TREM2 cleavage to restore efferocytosis mayrepresent an effective strategy to treat NASH.

DOI: 10.1016/j.immuni.2022.11.013

Source: https://www.cell.com/immunity/fulltext/S1074-7613(22)00603-3

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本期文章：《免疫》：Online/在线发表

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