Toll-Like Receptor-7 Signaling Promotes Nonalcoholic Steatohepatitis by Inhibiting Regulatory T Cells in Mice
Open accessAbstract
Toll-like receptor 7 (TLR7) signaling regulates the production of type 1 interferons (IFNs) and proinflammatory cytokines, such as tumor necrosis factor (TNF)-α, implicated in the control of regulatory T (Treg) cell activity. However, the mechanistic interplay between TLR7 signaling and Treg cells in nonalcoholic steatohepatitis (NASH) has not been elucidated. Our aim was to clarify the role of TLR7 signaling in the pathogenesis of NASH. Steatohepatitis was induced in wild-type (WT), TLR7-deficient, IFN-α/β receptor 1-deficient, and Treg cell-depleted mice. TLR7-deficient and IFN-α/β receptor 1-deficient mice were more protective to steatohepatitis than WT mice. Of interest, both TNF-α and type 1 IFN promoted apoptosis of Treg cells involved in the prevention of NASH. Indeed, Treg cell-depleted mice had aggravated steatohepatitis compared with WT mice. Finally, treatment with immunoregulatory sequence 661, an antagonist of TLR7, efficiently ameliorated NASH in vivo. These results demonstrate that TLR7 signaling can induce TNF-α production in Kupffer cells and type I IFN production in dendritic cells. These cytokines subsequently induce hepatocyte death and inhibit Treg cells activities, leading to the progression of NASH. Thus, manipulating the TLR7-Treg cell axis might be used as a novel therapeutic strategy to treat NASH.
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The inflammatory hepatic microenvironment with elevated TNF-α compromises Treg survival and promotes apoptosis during hepatocyte injury and MASH progression.
“In addition to IL-17, the inflammatory hepatic microenvironment characterized by elevated levels of TNF-α compromises the survival of Tregs and promotes their apoptosis during hepatocyte injury and the progression of MASH.”
From The double-edged sword of regulatory T cells in MASLD: from inflammation control to fibrosis promotion (2026) · cites this paper as Roh et al. 2018
The “TLR7-Induced Type I IFN and TNF-α Promotes Apoptosis of Treg Cells” section reports increased apoptosis of intrahepatic Tregs after TLR7 activation, reduced by treatment that inhibits TNF-α production. The Discussion links this pathway to hepatocyte injury and NASH progression. The evidence comes from mouse experiments involving TLR7 activation and also implicates type I IFN; it does not establish the claim as a general mechanism of MASH progression. (LLM, conf=0.84)
Experimental — accuracy not yet measuredDepletion of Tregs exacerbates hepatic inflammation in MASLD.
“The depletion of Tregs exacerbates hepatic inflammation in MASLD (Ma et al. 2007; Roh et al. 2018), suggesting that Tregs are crucial for regulating immune responses.”
From The double-edged sword of regulatory T cells in MASLD: from inflammation control to fibrosis promotion (2026) · cites this paper as Roh et al. 2018
The “Foxp3+ Treg Cells Prevent NASH Development” section reports more severe steatohepatitis and higher hepatic TNF-α in Treg-depleted mice. This supports the direction of the claim, but the evidence is limited to mice with diet-induced NASH; the citing sentence states it broadly for MASLD. (LLM, conf=0.85)
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Role of CD4+ T-cells in the pathology of non-alcoholic fatty liver disease and related diseases
Seike, T., Mizukoshi, E., & Kaneko, S. (2021) · Hepatoma Research · doi:10.20517/2394-5079.2021.46 · Cited by 6 · see citing works
Macrophage Notch1 signaling modulates regulatory T cells via the TGFB axis in early MASLD
Zhang, M.-Y., Li, K., Huang, X.-X., Xu, D., Zong, R., Hu, Q., Dong, X.-Y., Zhang, Q.-Y., Jiang, C., Ge, Y., et al. (2024) · JHEP Reports · doi:10.1016/j.jhepr.2024.101242 · Cited by 6 · see citing works
Zhao, J., Jeong, H., Yang, D., Tian, W., Kim, J.-W., Lim, C. W., & Lim, C. W. (2023) · International Immunopharmacology · doi:10.1016/j.intimp.2023.110238 · Cited by 5 · see citing works
Self-citationChen, Y., Jia, B., Tong, X., Yin, S., Ni, W., Zhao, Q., Shi, J., & Li, J. (2025) · Hepatology Communications · doi:10.1097/hc9.0000000000000864 · Cited by 4 · see citing works
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Programmed cell death and liver diseases
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Lee, S. E., Jo, M. G., Park, S. W., Kim, H. J., Yun, S. P., & Kim, J.-W. (2026) · Animal Cells and Systems · doi:10.1080/19768354.2026.2630463 · Cited by 2 · see citing works
“Damaged hepatocytes release damage-associated molecular patterns (DAMPs), which activate pattern recognition receptors on Kupffer cells (KCs) and dendritic cells (DCs), initiating a robust innate immune response (Garcia-Martinez et al. 2016; Kim et al. 2018; Roh et al. 2018).”
Self-citationImmune microenvironment and immunotherapy strategies in MAFLD-related hepatocellular carcinoma
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Mechanisms of Fibrogenesis in NASH
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Role of gut dysbiosis in chronic liver disease leading to fibrosis
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Plasmacytoid Dendritic Cells and Metabolic Disorders
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Research Progress on the Correlation between Lymphocytes and Non-Alcoholic Fatty Liver Disease
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The Roles of T Lymphocyte Subsets in the Pathogenesis of NAFLD
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Étude de la fonction de la DNASE1L3 en contexte auto-immun et anti-tumoral
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Toll-like receptor gene 7 and gene 9 in MASLD
Ahmed, A., Tahoon, M. A. H., Samy, L. A., Selim, M. A., Ashraf, S., Yones, A., Abdelhamid, W., Abdelghafour, R., Ibrahim, R., Mohamed, A. R., et al. (2026) · The Egyptian Journal of Internal Medicine · doi:10.1186/s43162-026-00648-5
- Authors
- Roh, Y. S., Kim, J. W., Park, S., Shon, C., Kim, S., Eo, S. K., Kwon, J. K., Lim, C. W., & Kim, B.
- Affiliations
- Chungbuk National University (KR)
- Jeonbuk National University (KR)
- Corresponding author
- Kim, Bumseok
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2018-11
- Volume
- 188
- Issue
- 11
- Pages
- 2574-2588
- ISSN
- 0002-9440 (ISSN-L)
- OpenAlex
- W2885324680
- Cited by
- 55
- References
- 52
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 9 · 2023: 5 · 2022: 9 · 2021: 9 · 2020: 8 · 2019: 3
- FWCI
- 3.92
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Research Foundation of Korea
- Ministry of Health and Welfare (HI17C2262)
- Ministry of Education
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- TLR7, nonalcoholic steatohepatitis, regulatory T cells, type I interferon, TNF-α, Kupffer cells, dendritic cells, hepatocyte apoptosis, Treg depletion, liver inflammation
- MeSH terms
- Animals, Cells, Cultured, Dendritic Cells, Interferon Type I, Kupffer Cells, Membrane Glycoproteins, Mice, Inbred C57BL, Tumor Necrosis Factor-alpha, Signal Transduction, Cytokines, Hepatocytes, T-Lymphocytes, Regulatory, Toll-Like Receptor 7, Mice, Non-alcoholic Fatty Liver Disease
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