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Expression of STING Is Increased in Liver Tissues From Patients With NAFLD and Promotes Macrophage-Mediated Hepatic Inflammation and Fibrosis in Mice.
Gastroenterology. 2018 12; 155(6):1971-1984.e4.G

Abstract

BACKGROUND & AIMS

Transmembrane protein 173 (TMEM173 or STING) signaling by macrophage activates the type I interferon-mediated innate immune response. The innate immune response contributes to hepatic steatosis and non-alcoholic fatty liver disease (NAFLD). We investigated whether STING regulates diet-induced in hepatic steatosis, inflammation, and liver fibrosis in mice.

METHODS

Mice with disruption of Tmem173 (STINGgt) on a C57BL/6J background, mice without disruption of this gene (controls), and mice with disruption of Tmem173 only in myeloid cells were fed a standard chow diet, a high-fat diet (HFD; 60% fat calories), or a methionine- and choline-deficient diet (MCD). Liver tissues were collected and analyzed by histology and immunohistochemistry. Bone marrow cells were isolated from mice, differentiated into macrophages, and incubated with 5,6-dimethylxanthenone-4-acetic acid (DMXAA; an activator of STING) or cyclic guanosine monophosphate-adenosine monophosphate (cGAMP). Macrophages or their media were applied to mouse hepatocytes or human hepatic stellate cells (LX2) cells, which were analyzed for cytokine expression, protein phosphorylation, and fat deposition (by oil red O staining after incubation with palmitate). We obtained liver tissues from patients with and without NAFLD and analyzed these by immunohistochemistry.

RESULTS

Non-parenchymal cells of liver tissues from patients with NAFLD had higher levels of STING than cells of liver tissues from patients without NAFLD. STINGgt mice and mice with disruption only in myeloid cells developed less severe hepatic steatosis, inflammation, and/or fibrosis after the HFD or MCD than control mice. Levels of phosphorylated c-Jun N-terminal kinase and p65 and mRNAs encoding tumor necrosis factor and interleukins 1B and 6 (markers of inflammation) were significantly lower in liver tissues from STINGgt mice vs control mice after the HFD or MCD. Transplantation of bone marrow cells from control mice to STINGgt mice restored the severity of steatosis and inflammation after the HFD. Macrophages from control, but not STINGgt, mice increased markers of inflammation in response to lipopolysaccharide and cGAMP. Hepatocytes and stellate cells cocultured with STINGgt macrophages in the presence of DMXAA or incubated with the medium collected from these macrophages had decreased fat deposition and markers of inflammation compared with hepatocytes or stellate cells incubated with control macrophages.

CONCLUSIONS

Levels of STING were increased in liver tissues from patients with NAFLD and mice with HFD-induced steatosis. In mice, loss of STING from macrophages decreased the severity of liver fibrosis and the inflammatory response. STING might be a therapeutic target for NAFLD.

Authors+Show Affiliations

Department of Nutrition and Food Science, Texas A&M University, College Station, Texas.Department of Nutrition and Food Science, Texas A&M University, College Station, Texas.Department of Nutrition and Food Science, Texas A&M University, College Station, Texas; Department of Endocrinology, First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Laboratory of Lipid & Glucose Metabolism, First Affiliated Hospital of Chongqing Medical University, Chongqing, China.Department of Nutrition and Food Science, Texas A&M University, College Station, Texas.Department of Nutrition and Food Science, Texas A&M University, College Station, Texas.Department of Nutrition and Food Science, Texas A&M University, College Station, Texas.Department of Nutrition and Food Science, Texas A&M University, College Station, Texas.Radiation Oncology, Veterinary Medical Teaching Hospital, Texas A&M University, College Station, Texas.Radiation Oncology, Veterinary Medical Teaching Hospital, Texas A&M University, College Station, Texas.Department of Endocrinology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.Department of Cardiology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.Department of Endocrinology, First Affiliated Hospital of Chongqing Medical University, Chongqing, China.Laboratory of Lipid & Glucose Metabolism, First Affiliated Hospital of Chongqing Medical University, Chongqing, China.Pathology, Baylor Scott & White Health, College Station, Texas.Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia.Research, Central Texas Veterans Health Care System, Temple, Texas; Department of Medical Physiology, Texas A&M University College of Medicine, Temple, Texas.Research, Central Texas Veterans Health Care System, Temple, Texas; Department of Medical Physiology, Texas A&M University College of Medicine, Temple, Texas.Research, Central Texas Veterans Health Care System, Temple, Texas; Department of Medical Physiology, Texas A&M University College of Medicine, Temple, Texas.Research, Central Texas Veterans Health Care System, Temple, Texas.Research, Central Texas Veterans Health Care System, Temple, Texas; Department of Medical Physiology, Texas A&M University College of Medicine, Temple, Texas. Electronic address: galpini@tamu.edu.Department of Nutrition and Food Science, Texas A&M University, College Station, Texas. Electronic address: cdwu@tamu.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

30213555

Citation

Luo, Xianjun, et al. "Expression of STING Is Increased in Liver Tissues From Patients With NAFLD and Promotes Macrophage-Mediated Hepatic Inflammation and Fibrosis in Mice." Gastroenterology, vol. 155, no. 6, 2018, pp. 1971-1984.e4.
Luo X, Li H, Ma L, et al. Expression of STING Is Increased in Liver Tissues From Patients With NAFLD and Promotes Macrophage-Mediated Hepatic Inflammation and Fibrosis in Mice. Gastroenterology. 2018;155(6):1971-1984.e4.
Luo, X., Li, H., Ma, L., Zhou, J., Guo, X., Woo, S. L., Pei, Y., Knight, L. R., Deveau, M., Chen, Y., Qian, X., Xiao, X., Li, Q., Chen, X., Huo, Y., McDaniel, K., Francis, H., Glaser, S., Meng, F., ... Wu, C. (2018). Expression of STING Is Increased in Liver Tissues From Patients With NAFLD and Promotes Macrophage-Mediated Hepatic Inflammation and Fibrosis in Mice. Gastroenterology, 155(6), 1971-e4. https://doi.org/10.1053/j.gastro.2018.09.010
Luo X, et al. Expression of STING Is Increased in Liver Tissues From Patients With NAFLD and Promotes Macrophage-Mediated Hepatic Inflammation and Fibrosis in Mice. Gastroenterology. 2018;155(6):1971-1984.e4. PubMed PMID: 30213555.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Expression of STING Is Increased in Liver Tissues From Patients With NAFLD and Promotes Macrophage-Mediated Hepatic Inflammation and Fibrosis in Mice. AU - Luo,Xianjun, AU - Li,Honggui, AU - Ma,Linqiang, AU - Zhou,Jing, AU - Guo,Xin, AU - Woo,Shih-Lung, AU - Pei,Ya, AU - Knight,Linda R, AU - Deveau,Michael, AU - Chen,Yanming, AU - Qian,Xiaoxian, AU - Xiao,Xiaoqiu, AU - Li,Qifu, AU - Chen,Xiangbai, AU - Huo,Yuqing, AU - McDaniel,Kelly, AU - Francis,Heather, AU - Glaser,Shannon, AU - Meng,Fanyin, AU - Alpini,Gianfranco, AU - Wu,Chaodong, Y1 - 2018/09/10/ PY - 2018/06/13/received PY - 2018/08/17/revised PY - 2018/09/04/accepted PY - 2018/9/15/pubmed PY - 2019/1/8/medline PY - 2018/9/15/entrez KW - Hepatic Stellate Cell KW - Interferon KW - Lipopolysaccharide KW - Nonalcoholic Steatohepatitis SP - 1971 EP - 1984.e4 JF - Gastroenterology JO - Gastroenterology VL - 155 IS - 6 N2 - BACKGROUND & AIMS: Transmembrane protein 173 (TMEM173 or STING) signaling by macrophage activates the type I interferon-mediated innate immune response. The innate immune response contributes to hepatic steatosis and non-alcoholic fatty liver disease (NAFLD). We investigated whether STING regulates diet-induced in hepatic steatosis, inflammation, and liver fibrosis in mice. METHODS: Mice with disruption of Tmem173 (STINGgt) on a C57BL/6J background, mice without disruption of this gene (controls), and mice with disruption of Tmem173 only in myeloid cells were fed a standard chow diet, a high-fat diet (HFD; 60% fat calories), or a methionine- and choline-deficient diet (MCD). Liver tissues were collected and analyzed by histology and immunohistochemistry. Bone marrow cells were isolated from mice, differentiated into macrophages, and incubated with 5,6-dimethylxanthenone-4-acetic acid (DMXAA; an activator of STING) or cyclic guanosine monophosphate-adenosine monophosphate (cGAMP). Macrophages or their media were applied to mouse hepatocytes or human hepatic stellate cells (LX2) cells, which were analyzed for cytokine expression, protein phosphorylation, and fat deposition (by oil red O staining after incubation with palmitate). We obtained liver tissues from patients with and without NAFLD and analyzed these by immunohistochemistry. RESULTS: Non-parenchymal cells of liver tissues from patients with NAFLD had higher levels of STING than cells of liver tissues from patients without NAFLD. STINGgt mice and mice with disruption only in myeloid cells developed less severe hepatic steatosis, inflammation, and/or fibrosis after the HFD or MCD than control mice. Levels of phosphorylated c-Jun N-terminal kinase and p65 and mRNAs encoding tumor necrosis factor and interleukins 1B and 6 (markers of inflammation) were significantly lower in liver tissues from STINGgt mice vs control mice after the HFD or MCD. Transplantation of bone marrow cells from control mice to STINGgt mice restored the severity of steatosis and inflammation after the HFD. Macrophages from control, but not STINGgt, mice increased markers of inflammation in response to lipopolysaccharide and cGAMP. Hepatocytes and stellate cells cocultured with STINGgt macrophages in the presence of DMXAA or incubated with the medium collected from these macrophages had decreased fat deposition and markers of inflammation compared with hepatocytes or stellate cells incubated with control macrophages. CONCLUSIONS: Levels of STING were increased in liver tissues from patients with NAFLD and mice with HFD-induced steatosis. In mice, loss of STING from macrophages decreased the severity of liver fibrosis and the inflammatory response. STING might be a therapeutic target for NAFLD. SN - 1528-0012 UR - https://www.unboundmedicine.com/medline/citation/30213555/Expression_of_STING_Is_Increased_in_Liver_Tissues_From_Patients_With_NAFLD_and_Promotes_Macrophage_Mediated_Hepatic_Inflammation_and_Fibrosis_in_Mice_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0016-5085(18)34959-X DB - PRIME DP - Unbound Medicine ER -