STING expression in monocyte-derived macrophages is associated with the progression of liver inflammation and fibrosis in patients with nonalcoholic fatty liver disease
STING expression in monocyte-derived macrophages is associated with the progression of liver inflammation and fibrosis in patients with nonalcoholic fatty liver disease
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单核细胞源性巨噬细胞中 STING 的表达与非酒精性脂肪肝患者肝脏炎症和纤维化的进展相关
DOI：
10.1038/s41374-019-0342-6
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发表时间：
2020-04-01
影响因子：
5
通讯作者：
Wei, Lai
中科院分区：
文献类型：
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作者：
Wang, Xiaoxiao;Rao, Huiying;Wei, Lai
巨噬细胞中干扰素基因刺激因子（STING）在非酒精性脂肪肝（NAFLD）的进展中起着至关重要的作用。然而，缺乏来自大量患者样本的证据来证实STING在NAFLD中的有害作用。此外，与NAFLD相关的sting表达细胞的来源仍有待明确表征。为了研究人类受试者中STING的表达及其与NAFLD进展的相关性，我们的研究涉及了来自98名NAFLD受试者和8名对照组的肝脏样本。分析非实质肝细胞中STING和p-TBK1的表达与NAFLD病理特征的相关性。与对照组相比，非酒精性脂肪性肝炎（NASH）患者肝脏中STING（+）细胞数量增加，尤其是合并纤维化的NASH患者肝门道中（p < 0.05）。NASH患者肝脏中STING（+）细胞数量随炎症分级和纤维化分期加重而增加（p < 0.05）。STING主要在巨噬细胞中表达，包括单核细胞源性巨噬细胞（CCR2（+）、S100A9(+)）、Kupffer细胞（CD68(+)）和CD163（+）巨噬细胞。与对照组相比，NASH合并纤维化患者肝脏中STING(+)/CCR2（+）和STING(+)/S100A9（+）细胞数量显著增加，且与肝脏炎症分级和纤维化分期呈正相关（p < 0.05）。然而，NASH晚期纤维化患者肝脏中STING(+)/CD68（+）和STING(+)/CD163（+）细胞数量显著增加，且仅与纤维化分期加重相关（p < 0.05）。此外，与对照组相比，NASH患者表现出明显增加的STING(+)/p-TBK1（+）细胞数量。在共培养体系中，巨噬细胞激活STING后，THP1巨噬细胞中p- tbk1和IL1 β、IL6 mrna的表达量以及LX2细胞中α - sma的表达量和Col1a1、Fn、TGF β 1 mrna的表达量均显著升高（p < 0.05）。因此，在momf中增加的STING表达似乎是NAFLD进展的指示，STING可能是NAFLD治疗的新靶点。肝组织中干扰素刺激因子基因（STING）的表达与人类非酒精性脂肪性肝病的进展有关。具体来说，表达sting的巨噬细胞，特别是单核细胞来源的巨噬细胞，与肝脏炎症和/或纤维化进展的程度呈正相关，这似乎是由巨噬细胞中STING-TBK1信号通路的激活介导的。
The stimulator of interferon genes (STING) in macrophages plays a crucial role in nonalcoholic fatty liver disease (NAFLD) progression. However, there is a lack of evidence from large samples of patients to validate a deleterious role for STING in NAFLD. Moreover, sources of STING-expressing cells that are related to NAFLD remain to be definitively characterized. To investigate STING expression and explore its correlation with NAFLD progression in human subjects, our study involved liver samples from 98 NAFLD subjects and 8 controls. STING and p-TBK1 expression in nonparenchymal liver cells was analyzed and correlated with NAFLD pathological features. Numbers of STING(+) cells were increased in livers from nonalcoholic steatohepatitis (NASH) patients compared with controls, especially in the liver portal tract of NASH patients with fibrosis (p < 0.05). Moreover, numbers of STING(+) cells in livers of NASH patients were increased with aggravation of inflammation grade and fibrosis stage (p < 0.05). STING was mainly expressed in macrophages, including monocyte-derived macrophages (CCR2(+), S100A9(+)), Kupffer cells (CD68(+)) and CD163(+) macrophages. Compared with controls, numbers of STING(+)/CCR2(+) and STING(+)/S100A9(+) cells were significantly increased in livers from NASH patients with fibrosis and positively correlated with liver inflammation grade and fibrosis stage (p < 0.05). However, numbers of STING(+)/CD68(+) and STING(+)/CD163(+) cells were significantly increased in livers from NASH patients with advanced fibrosis and correlated only with aggravation of fibrosis stage (p < 0.05). Furthermore, compared with controls, NASH patients exhibited significantly increased STING(+)/p-TBK1(+) cell numbers. In a coculture system, the amount of p-TBK1 and the mRNAs of IL1 beta and IL6 in THP1 macrophages, as well as the amount of alpha-SMA and the mRNAs of Col1a1, Fn and TGF beta 1 in LX2 cells were significantly increased upon STING activation in macrophages (p < 0.05). Therefore, increased STING expression in MoMFs appears to be indicative of NAFLD progression, and STING could be a new target for NAFLD therapy.The expression of the stimulator of interferon genes (STING) in liver tissues is associated with the progression of human nonalcoholic fatty liver disease. Specifically, STING-expressing macrophages, in particular, monocyte-derived macrophages, are positively correlated with the degree of liver inflammation and/or fibrosis progression, which appeared to be mediated by the activation of the STING-TBK1 signaling pathway in macrophage.