STING expression in monocyte-derived macrophages is associated with the progression of liver inflammation and fibrosis in patients with nonalcoholic fatty liver disease

• Published in: Laboratory investigation Vol. 100; no. 4; pp. 542 - 552
• Main Authors: Wang, Xiaoxiao, Rao, Huiying, Zhao, Jingmin, Wee, Aileen, Li, Xiaohe, Fei, Ran, Huang, Rui, Wu, Chaodong, Liu, Feng, Wei, Lai
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.04.2020; Nature Publishing Group US; Nature Publishing Group
• Subjects: 13; 13/51; 14; 14/63; 692/699/1503/1607/2750; 692/699/1503/1607/2751; Adult; Aged; CCR2 protein; CD163 antigen; Cell activation; Collagen (type I); Correlation analysis; Disease Progression; Fatty liver; Female; Fibrosis; Gene expression; Genes; Hepatitis - metabolism; Hepatocytes; Humans; Inflammation; Interferon; Interleukin 1; Interleukin 6; Kupffer cells; Laboratory Medicine; Liver; Liver - metabolism; Liver - pathology; Liver Cirrhosis - metabolism; Liver diseases; Macrophages; Macrophages - metabolism; Male; Medicine; Medicine & Public Health; Membrane Proteins - analysis; Membrane Proteins - metabolism; Middle Aged; Monocyte chemoattractant protein 1; Monocytes; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; Pathology; Signal transduction; Stimulators; Transforming growth factor-b1; Young Adult
• ISSN: 0023-6837; 1530-0307; 1530-0307
• DOI: 10.1038/s41374-019-0342-6

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.