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Gastroenterology. 2018 Dec;155(6):1971-1984.e4. doi: 10.1053/j.gastro.2018.09.010. Epub 2018 Sep 10.

Expression of STING Is Increased in Liver Tissues From Patients With NAFLD and Promotes Macrophage-Mediated Hepatic Inflammation and Fibrosis in Mice.

Author information

1
Department of Nutrition and Food Science, Texas A&M University, College Station, Texas.
2
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.
3
Radiation Oncology, Veterinary Medical Teaching Hospital, Texas A&M University, College Station, Texas.
4
Department of Endocrinology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
5
Department of Cardiology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
6
Department of Endocrinology, First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
7
Laboratory of Lipid & Glucose Metabolism, First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
8
Pathology, Baylor Scott & White Health, College Station, Texas.
9
Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia.
10
Research, Central Texas Veterans Health Care System, Temple, Texas; Department of Medical Physiology, Texas A&M University College of Medicine, Temple, Texas.
11
Research, Central Texas Veterans Health Care System, Temple, Texas.
12
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.
13
Department of Nutrition and Food Science, Texas A&M University, College Station, Texas. Electronic address: cdwu@tamu.edu.

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.

KEYWORDS:

Hepatic Stellate Cell; Interferon; Lipopolysaccharide; Nonalcoholic Steatohepatitis

PMID:
30213555
PMCID:
PMC6279491
[Available on 2019-12-01]
DOI:
10.1053/j.gastro.2018.09.010
[Indexed for MEDLINE]

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