Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, 100044, Beijing, China.
Department of Pathology, The Fifth Medical Center of PLA General Hospital, 100039, Beijing, China.
Lab Invest. 2020 Apr;100(4):542-552. doi: 10.1038/s41374-019-0342-6. Epub 2019 Nov 19.
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 IL1β and IL6 in THP1 macrophages, as well as the amount of α-SMA and the mRNAs of Col1a1, Fn and TGFβ1 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.
干扰素基因刺激物（STING）在巨噬细胞中发挥着关键作用，在非酒精性脂肪性肝病（NAFLD）的进展中起着关键作用。然而，缺乏来自大量患者的证据来验证 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描述。为了研究 STING 表达并探讨其与人类 NAFLD 进展的相关性，我们的研究涉及 98 例 NAFLD 患者和 8 例对照的肝组织样本。分析了非实质细胞中的 STING 和 p-TBK1 表达，并与 NAFLD 病理特征相关。与对照组相比，非酒精性脂肪性肝炎（NASH）患者的肝脏中 STING 细胞数量增加，尤其是纤维化 NASH 患者的肝门区（p<0.05）。此外，NASH 患者肝脏中 STING 细胞的数量随着炎症程度和纤维化阶段的加重而增加（p<0.05）。STING 主要表达于巨噬细胞，包括单核细胞衍生的巨噬细胞（CCR2、S100A9）、枯否细胞（CD68）和 CD163 巨噬细胞。与对照组相比，纤维化 NASH 患者肝组织中 STING/CCR2 和 STING/S100A9 细胞数量显著增加，并与肝炎症程度和纤维化阶段呈正相关（p<0.05）。然而，在晚期纤维化的 NASH 患者肝脏中，STING/CD68 和 STING/CD163 细胞数量显著增加，仅与纤维化阶段的加重相关（p<0.05）。此外，与对照组相比，NASH 患者的 STING/p-TBK1 细胞数量显著增加。在共培养体系中，当巨噬细胞中的 STING 被激活时，THP1 巨噬细胞中的 p-TBK1 量和 IL1β 和 IL6 的 mRNAs，以及 LX2 细胞中的 α-SMA 和 Col1a1、Fn 和 TGFβ1 的 mRNAs 的量均显著增加（p<0.05）。因此，MoMFs 中 STING 表达的增加似乎预示着 NAFLD 的进展，STING 可能成为 NAFLD 治疗的新靶点。
