Expression of STING Is Increased in Liver Tissues From Patients With NAFLD and Promotes Macrophage-Mediated Hepatic Inflammation and Fibrosis in Mice
Open accessAbstract
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 (STING gt) 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. STING gt 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 STING gt mice vs control mice after the HFD or MCD. Transplantation of bone marrow cells from control mice to STING gt mice restored the severity of steatosis and inflammation after the HFD. Macrophages from control, but not STING gt, mice increased markers of inflammation in response to lipopolysaccharide and cGAMP. Hepatocytes and stellate cells cocultured with STING gt 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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Circulating mitochondrial DNA is a powerful inflammatory signal in NASH that activates STING in macrophages.
“Circulating mitochondrial DNA is a powerful inflammatory signal in NASH that activates the antiviral response molecule, STimulator of Interferon Genes (STING), in macrophages (85, 86).”
From Hepatic Stellate Cell-Immune Interactions in NASH (2022) · cites this paper as [85]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Younossi, Z. M., Koenig, A. B., Abdelatif, D., Fazel, Y., Henry, L., & Wymer, M. (2016) · Hepatology · doi:10.1002/hep.28431 · Cited by 10,781 · see citing works
Chalasani, N., Younossi, Z., Lavine, J. E., Charlton, M., Cusi, K., Rinella, M., Harrison, S. A., Brunt, E. M., & Sanyal, A. J. (2018) · Hepatology · doi:10.1002/hep.29367 · Cited by 7,239 · see citing works
Cyclic GMP-AMP Synthase Is a Cytosolic DNA Sensor That Activates the Type I Interferon Pathway
Sun, L., Wu, J., Du, F., Chen, X., & Chen, Z. J. (2013) · Science · doi:10.1126/science.1232458 · Cited by 4,996 · see citing works
Self-citationSTING is an endoplasmic reticulum adaptor that facilitates innate immune signalling
Ishikawa, H., & Barber, G. N. (2008) · Nature · doi:10.1038/nature07317 · Cited by 3,576 · see citing works
Estes, C., Razavi, H. A., Loomba, R. S., Younossi, Z. M., & Sanyal, A. J. (2017) · Hepatology · doi:10.1002/hep.29466 · Cited by 2,416 · see citing works
Nonalcoholic Fatty Liver Disease: From Steatosis to Cirrhosis
Farrell, G. C., & Larter, C. Z. (2006) · Hepatology · doi:10.1002/hep.20973 · Cited by 2,413 · see citing works
Deng, L., Liang, H., Xu, M., Yang, X., Burnette, B., Arina, A., Li, X.-D., Mauceri, H., Beckett, M., Darga, T., et al. (2014) · Immunity · doi:10.1016/j.immuni.2014.10.019 · Cited by 2,182 · see citing works
Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation
Liu, S., Cai, X., Wu, J., Cong, Q., Chen, X., Li, T., Du, F., Ren, J., Wu, Y.-T., Grishin, N. V., et al. (2015) · Science · doi:10.1126/science.aaa2630 · Cited by 1,927 · see citing works
Self-citationNonalcoholic Fatty Liver Disease and Hepatocellular Carcinoma: A Weighty Connection
Starley, B. Q., Calcagno, C. J., & Harrison, S. A. (2010) · Hepatology · doi:10.1002/hep.23594 · Cited by 1,340 · see citing works
Lumeng, C. N., DeYoung, S. M., Bodzin, J. L., & Saltiel, A. R. (2007) · Diabetes · doi:10.2337/db06-1076 · Cited by 1,016 · see citing works
Triggering and resolution of inflammation in NASH
Schuster, S., Cabrera, D., Arrese, M., & Feldstein, A. E. (2018) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-018-0009-6 · Cited by 943 · see citing works
Alternative M2 Activation of Kupffer Cells by PPARδ Ameliorates Obesity-Induced Insulin Resistance
Odegaard, J. I., Ricardo-González, R. R., Eagle, A. R., Vats, D., Morel, C. R., Goforth, M. H., Subramanian, V., Mukundan, L., Ferrante, A. W., & Chawla, A. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.04.003 · Cited by 840 · see citing works
Younossi, Z. M., Otgonsuren, M., Henry, L., Venkatesan, C., Mishra, A., Erario, M., & Hunt, S. (2015) · Hepatology · doi:10.1002/hep.28123 · Cited by 802 · see citing works
Wentworth, J. M., Naselli, G., Brown, W. A., Doyle, L., Phipson, B., Smyth, G. K., Wabitsch, M., O’Brien, P. E., & Harrison, L. C. (2010) · Diabetes · doi:10.2337/db09-0287 · Cited by 609 · see citing works
Huang, W., Metlakunta, A., Dedousis, N., Zhang, P., Sipula, I., Dube, J. J., Scott, D. K., & O'Doherty, R. M. (2010) · Diabetes · doi:10.2337/db09-0016 · Cited by 520 · see citing works
Petrasek, J., Iracheta‐Vellve, A., Csák, T., Satishchandran, A., Kodys, K., Kurt‐Jones, E. A., Fitzgerald, K. A., & Szabó, G. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1308331110 · Cited by 452 · see citing works
Conlon, J. E., Burdette, D. L., Sharma, S., Bhat, N., Thompson, M., Jiang, Z., Rathinam, V. A. K., Monks, B. G., Jin, T., Xiao, T. S., et al. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1300097 · Cited by 441 · see citing works
Obesity and hepatocellular carcinoma
Caldwell, S. H., Crespo, D. M., Kang, H. S., & Al‐Osaimi, A. M. S. (2004) · Gastroenterology · doi:10.1053/j.gastro.2004.09.021 · Cited by 396 · see citing works
Steatosis: Co-factor in Other Liver Diseases *
Powell, E. E., Jonsson, J. R., & Clouston, A. D. (2005) · Hepatology · doi:10.1002/hep.20750 · Cited by 372 · see citing works
Cutting Edge: Activation of STING in T Cells Induces Type I IFN Responses and Cell Death
Larkin, B., Ilyukha, V., Sorokin, M., Buzdin, A., Vannier, E., & Poltorak, A. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1601999 · Cited by 361 · see citing works
Mao, Y., Luo, W., Zhang, L., Wu, W., Yuan, L., Xu, H. Y., Song, J., Fujiwara, K., Abe, J., LeMaire, S. A., et al. (2017) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.117.309017 · Cited by 307 · see citing works
TBK1 at the Crossroads of Inflammation and Energy Homeostasis in Adipose Tissue
Zhao, P., Wong, K. I., Sun, X., Reilly, S. M., Uhm, M., Liao, Z., Skorobogatko, Y. V., & Saltiel, A. R. (2018) · Cell · doi:10.1016/j.cell.2018.01.007 · Cited by 252 · see citing works
Qiao, J. T., Cui, C., Qing, L., Wang, L., He, T., Yan, F., Liu, F. Q., Shen, Y. H., Hou, X., & Chen, L. (2017) · Metabolism · doi:10.1016/j.metabol.2017.09.010 · Cited by 239 · see citing works
Mechanisms of Disease: pathogenesis of nonalcoholic fatty liver disease
Sanyal, A. J. (2005) · Nature Clinical Practice Gastroenterology & Hepatology · doi:10.1038/ncpgasthep0084 · Cited by 216 · see citing works
Kodama, Y., Kisseleva, T., Iwaisako, K., Miura, K., Taura, K., Minicis, S. D., Österreicher, C. H., Schnabl, B., Seki, E., & Brenner, D. A. (2009) · Gastroenterology · doi:10.1053/j.gastro.2009.06.045 · Cited by 195 · see citing works
Woo, S., Xu, H., Li, H., Zhao, Y., Hu, X., Zhao, J., Guo, X., Guo, T., Botchlett, R. E., Qi, T., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0091111 · Cited by 194 · see citing works
Self-citationStienstra, R., Duval, C., Keshtkar, S., van der Laak, J. A. W. M., Kersten, S., & Müller, M. M. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m710314200 · Cited by 189 · see citing works
Lack of immunological DNA sensing in hepatocytes facilitates hepatitis B virus infection
Thomsen, M. K., Nandakumar, R., Stadler, D., Malo, A., Valls, R. M., Wang, F., Reinert, L. S., Dagnæs‐Hansen, F., Hollensen, A. K., Mikkelsen, J. G., et al. (2016) · Hepatology · doi:10.1002/hep.28685 · Cited by 187 · see citing works
Paijo, J., Döring, M., Spanier, J., Grabski, E., Nooruzzaman, M., Schmidt, T., Witte, G., Messerle, M., Hornung, V., Kaever, V., et al. (2016) · PLoS Pathogens · doi:10.1371/journal.ppat.1005546 · Cited by 181 · see citing works
IRF3 promotes adipose inflammation and insulin resistance and represses browning
Kumari, M., Wang, X., Lantier, L., Lyubetskaya, A., Eguchi, J., Kang, S., Tenen, D. E., Roh, H. C., Kong, X., Kazak, L., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci86080 · Cited by 180 · see citing works
Sphingosine kinase 1 promotes liver fibrosis by preventing miR‐19b‐3p‐mediated inhibition of CCR2
Lan, T., Li, C., Yang, G., Sun, Y., Zhuang, L., Ou, Y., Li, H., Wang, G., Kisseleva, T., Brenner, D., et al. (2018) · Hepatology · doi:10.1002/hep.29885 · Cited by 153 · see citing works
Self-citationPalmitoleate Induces Hepatic Steatosis but Suppresses Liver Inflammatory Response in Mice
Guo, X., Li, H., Xu, H., Halim, V., Zhang, W., Wang, H., Ong, K. T., Woo, S., Walzem, R. L., Mashek, D. G., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0039286 · Cited by 149 · see citing works
Self-citationImmature myeloid cells induced by a high-fat diet contribute to liver inflammation #
Deng, Z., Liu, Y., Liu, C., Xiang, X., Wang, J., Cheng, Z., Shah, S. V., Zhang, S., Zhang, L., Zhuang, X., et al. (2009) · Hepatology · doi:10.1002/hep.23148 · Cited by 149 · see citing works
Iracheta‐Vellve, A., Petrasek, J., Gyöngyösi, B., Satishchandran, A., Lowe, P., Kodys, K., Catalano, D. E., Calenda, C. D., Kurt‐Jones, E. A., Fitzgerald, K. A., et al. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.736991 · Cited by 149 · see citing works
Cho, C., Park, H., Ho, A., Semple, I. A., Kim, B. Y., Jang, I., Park, H., Reilly, S. M., Saltiel, A. R., & Lee, J. H. (2017) · Hepatology · doi:10.1002/hep.29742 · Cited by 116 · see citing works
Guo, T., Woo, S., Guo, X., Li, H., Zheng, J., Botchlett, R. E., Liu, M., Pei, Y., Xu, H., Cai, Y., et al. (2016) · Scientific Reports · doi:10.1038/srep22612 · Cited by 111 · see citing works
Self-citationNAFLD, Obesity, and Bariatric Surgery
Angulo, P. (2006) · Gastroenterology · doi:10.1053/j.gastro.2006.03.041 · Cited by 106 · see citing works
Gandhi, C. R., Chaillet, J. R., Nalesnik, M. A., Kumar, S., Dangi, A., Demetris, A. J., Ferrell, R. E., Wu, T., Divanovic, S., Stankeiwicz, T., et al. (2014) · Gastroenterology · doi:10.1053/j.gastro.2014.10.008 · Cited by 99 · see citing works
Xu, H., Li, H., Woo, S., Kim, S.-M., Shende, V. R., Neuendorff, N., Guo, X., Guo, T., Qi, T., Pei, Y., et al. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.539601 · Cited by 99 · see citing works
Self-citationHuo, Y., Guo, X., Li, H., Wang, H., Zhang, W., Wang, Y., Zhou, H., Gao, Z., Telang, S., Chesney, J. A., et al. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.058446 · Cited by 87 · see citing works
Self-citationCai, Y., Li, H., Liu, M., Pei, Y., Zheng, J., Zhou, J., Luo, X., Huang, W., Ma, L., Yang, Q., et al. (2018) · Hepatology · doi:10.1002/hep.29777 · Cited by 78 · see citing works
Self-citationExpression of microRNA‐155 in inflammatory cells modulates liver injury
Blaya, D., Aguilar‐Bravo, B., Hao, F., Casacuberta‐Serra, S., Coll, M., Perea, L., Vallverdú, J., Graupera, I., Pose, E., Llovet, L. P., et al. (2018) · Hepatology · doi:10.1002/hep.29833 · Cited by 69 · see citing works
Huo, Y., Guo, X., Li, H., Xu, H., Halim, V., Zhang, W., Wang, H., Fan, Y.-Y., Ong, K. T., Woo, S., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.370379 · Cited by 61 · see citing works
Self-citationGuo, X., Shu, C., Li, H., Pei, Y., Woo, S., Zheng, J., Liu, M., Xu, H., Botchlett, R. E., Guo, T., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-05884-y · Cited by 29 · see citing works
Self-citationThiazolidinediones for NASH—one pill doesn't fix everything
Neuschwander‐Tetri, B. A. (2010) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2010.50 · Cited by 11 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Mechanisms and disease consequences of nonalcoholic fatty liver disease
Loomba, R., Friedman, S. L., & Shulman, G. I. (2021) · Cell · doi:10.1016/j.cell.2021.04.015 · Cited by 2,002 · see citing works
DNA sensing by the cGAS–STING pathway in health and disease
Motwani, M., Pesiridis, S., & Fitzgerald, K. A. (2019) · Nature Reviews Genetics · doi:10.1038/s41576-019-0151-1 · Cited by 1,467 · see citing works
Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response
Wan, D., Jiang, W., & Hao, J. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00615 · Cited by 270 · see citing works
Pharmacological modulation of nucleic acid sensors - therapeutic potential and persisting obstacles
Vanpouille-Box, C., Hoffmann, J. A., & Galluzzi, L. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0043-2 · Cited by 183 · see citing works
Mapping the molecular signatures of diet-induced NASH and its regulation by the hepatokine Tsukushi
Xiong, X., Wang, Q., Wang, S., Zhang, J., Liu, T., Guo, L., Yu, Y., & Lin, J. D. (2019) · Molecular Metabolism · doi:10.1016/j.molmet.2018.12.004 · Cited by 100 · see citing works
Hepatic Stellate Cell-Immune Interactions in NASH
Carter, J. K., & Friedman, S. L. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.867940 · Cited by 79 · see citing works
Immunopathogenic mechanisms and immunoregulatory therapies in MASLD
He, Y., Chen, Y., Qian, S., van Der Merwe, S., Dhar, D., Brenner, D. A., & Tacke, F. (2025) · Cellular & Molecular Immunology · doi:10.1038/s41423-025-01307-5 · Cited by 81 · see citing works
Self-citationHepatocytes demarcated by EphB2 contribute to the progression of nonalcoholic steatohepatitis
Xiao, Y., Batmanov, K., Hu, W., Zhu, K., Tom, A. Y., Guan, D., Jiang, C., Cheng, L., McCright, S. J., Yang, E. C., et al. (2023) · Science Translational Medicine · doi:10.1126/scitranslmed.adc9653 · Cited by 69 · see citing works
Inflammatory signaling in NASH driven by hepatocyte mitochondrial dysfunctions
Myint, M., Oppedisano, F., De Giorgi, V., Kim, B.-M., Marincola, F. M., Alter, H. J., & Nesci, S. (2023) · Journal of Translational Medicine · doi:10.1186/s12967-023-04627-0 · Cited by 61 · see citing works
Lee, J., Kim, C. M., Cha, J. H., Park, J. Y., Yu, Y. S., Wang, H. J., Sung, P. S., Jung, E. S., & Bae, S. H. (2022) · Cells · doi:10.3390/cells11213387 · Cited by 16 · see citing works
Novel regulators of hepatic macrophages in liver fibrosis
Tang, X., Bai, M., Du, X., Wang, H., Liu, M., Fu, X., Zhang, H., Liang, S., & Wang, L. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1705503 · Cited by 12 · see citing works
Strategies to promote liver fibrosis amelioration with involvement of restorative macrophages
Aquino, J. B. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1792423 · Cited by 1 · see citing works
- Authors
- 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., Alpini, G., & Wu, C.
- Affiliations
- Texas A&M University (US)
- The Affiliated Yongchuan Hospital of Chongqing Medical University (CN)
- Third Affiliated Hospital of Sun Yat-sen University (CN)
- Baylor Scott & White Health (US)
- Augusta University (US)
- Central Texas Veterans Health Care System (US)
- Corresponding author
- Alpini, Gianfranco
- Wu, Chaodong
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2018-12
- Volume
- 155
- Issue
- 6
- Pages
- 1971-1984.e4
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC6279491
- OpenAlex
- W2891103014
- Cited by
- 415
- References
- 45
- Citations by year
- 2026: 56 · 2025: 68 · 2024: 64 · 2023: 61 · 2022: 64 · 2021: 53 · 2020: 29 · 2019: 18 · 2018: 2
- FWCI
- 19.89
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Gastroenterology (acceptedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Diabetes Association (1-17-IBS-145)
- National Institute of Food and Agriculture
- National Institutes of Health (DK095862)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Keywords
- STING, non-alcoholic fatty liver disease, hepatic steatosis, liver inflammation, liver fibrosis, macrophages, innate immunity, type I interferon, c-Jun N-terminal kinase, high-fat diet, methionine-choline-deficient diet, hepatic stellate cells, bone marrow transplantation
- MeSH terms
- STING Protein, Animals, Hepatitis, Humans, Immunity, Innate, Interferon Type I, Liver, Liver Cirrhosis, Macrophages, Membrane Proteins, Mice, Inbred C57BL, Mice, Non-alcoholic Fatty Liver Disease
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
