Toll-Like Receptor 9 Promotes Steatohepatitis by Induction of Interleukin-1β in Mice
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Background & aims Development of nonalcoholic steatohepatitis (NASH) involves the innate immune system and is mediated by Kupffer cells and hepatic stellate cells (HSCs). Toll-like receptor 9 (TLR9) is a pattern recognition receptor that recognizes bacteria-derived cytosine phosphate guanine (CpG)-containing DNA and activates innate immunity. We investigated the role of TLR9 signaling and the inflammatory cytokine interleukin-1beta (IL-1beta) in steatohepatitis, fibrosis, and insulin resistance.Methods Wild-type (WT), TLR9(-/-), IL-1 receptor (IL-1R)(-/-), and MyD88(-/-) mice were fed a choline-deficient amino acid-defined (CDAA) diet for 22 weeks and then assessed for steatohepatitis, fibrosis, and insulin resistance. Lipid accumulation and cell death were assessed in isolated hepatocytes. Kupffer cells and HSCs were isolated to assess inflammatory and fibrogenic responses, respectively.Results The CDAA diet induced NASH in WT mice, characterized by steatosis, inflammation, fibrosis, and insulin resistance. TLR9(-/-) mice showed less steatohepatitis and liver fibrosis than WT mice. Among inflammatory cytokines, IL-1beta production was suppressed in TLR9(-/-) mice. Kupffer cells produced IL-1beta in response to CpG oligodeoxynucleotide. IL-1beta but not CpG-oligodeoxynucleotides, increased lipid accumulation in hepatocytes. Lipid accumulation in hepatocytes led to nuclear factor-kappaB inactivation, resulting in cell death in response to IL-1beta. IL-1beta induced fibrogenic responses in HSCs, including secretion of tissue inhibitor of metalloproteinase-1. IL-1R(-/-) mice had reduced steatohepatitis and fibrosis, compared with WT mice. Mice deficient in MyD88, an adaptor molecule for TLR9 and IL-1R signaling, also had reduced steatohepatitis and fibrosis. TLR9(-/-), IL-1R(-/-), and MyD88(-/-) mice had less insulin resistance than WT mice on the CDAA diet.Conclusions In a mouse model of NASH, TLR9 signaling induces production of IL-1beta by Kupffer cells, leading to steatosis, inflammation, and fibrosis.
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Similar results indicating a pathogenetic role of TLR have been obtained for TLR9 using the choline-deficient L-amino acid-defined diet model of NASH.
“Similar results indicating a pathogenetic role of TLR have been obtained also for TLR9 using the choline-deficient L-amino acid-defined diet model of NASH [283].”
From Gut-pancreas-liver Axis as a target for treatment of NAFLD/NASH (2020) · cites this paper as [283]
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- Authors
- Miura, K., Kodama, Y., Inokuchi, S., Schnabl, B., Aoyama, T., Ohnishi, H., Olefsky, J. M., Brenner, D. A., & Seki, E.
- Affiliations
- Akita University (JP)
- University of California San Diego (US)
- Corresponding author
- Miura, Kouichi
- Seki, Ekihiro
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2010-07
- Volume
- 139
- Issue
- 1
- Pages
- 323-334.e7
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC4631262
- OpenAlex
- W2106549878
- Cited by
- 741
- References
- 55
- Citations by year
- 2026: 22 · 2025: 29 · 2024: 47 · 2023: 36 · 2022: 50 · 2021: 53 · 2020: 69 · 2019: 61 · 2018: 56 · 2017: 48 · 2016: 44 · 2015: 63 · 2014: 48 · 2013: 50 · 2012: 27
- FWCI
- 26.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Association for the Study of Liver Diseases
- National Institute on Alcohol Abuse and Alcoholism
- National Institutes of Health (5R01DK072237, 5R01GM041804)
- Takeda Science Foundation
- 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
- TLR9, nonalcoholic steatohepatitis, IL-1β, Kupffer cells, hepatic stellate cells, liver fibrosis, insulin resistance, innate immunity, MyD88, IL-1 receptor, CpG oligodeoxynucleotides, hepatocyte lipid accumulation, hepatocyte death, NF-κB
- MeSH terms
- Animals, Choline Deficiency, Fatty Liver, Insulin Resistance, Kupffer Cells, Liver Cirrhosis, Experimental, Male, Mice, Inbred C57BL, RNA, Messenger, Signal Transduction, Lipid Metabolism, Toll-Like Receptor 9, Mice, Interleukin-1beta, Myeloid Differentiation Factor 88, Hepatic Stellate Cells
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