The critical role of toll‐like receptor (TLR) 4 in alcoholic liver disease is independent of the common TLR adapter MyD88†
Open accessAbstract
UNLABELLED: The Toll-like receptor 4 (TLR4) that recognizes endotoxin, a trigger of inflammation in alcoholic liver disease (ALD), activates two signaling pathways utilizing different adapter molecules: the common TLR adapter, myeloid differentiation factor 88 (MyD88), or Toll/interleukin immune-response-domain-containing adaptor inducing interferon (IFN)-beta. The MyD88 pathway induces proinflammatory cytokine activation, a critical mediator of ALD. Here we evaluated the role of MyD88 in alcohol-induced liver injury in wild-type, TLR2-deficient, TLR4-deficient, or MyD88-deficient (knockout [KO]) mice after administration of the Lieber-De-Carli diet (4.5% volume/volume ethanol) or an isocaloric liquid control diet for 5 weeks. Alcohol feeding resulted in a significant increase in serum alanine aminotransferase levels, liver steatosis and triglyceride levels suggesting liver damage in WT, TLR2-KO, and MyD88-KO but not in TLR4-KO mice. Expression of inflammatory mediators (tumor necrosis factor-alpha and interleukin-6) and TLR4 coreceptors (CD14 and MD2) was significantly higher in livers of alcohol-fed WT, TLR2-KO, or MyD88-KO, but not in TLR4-KO mice, compared to controls. Reactive oxygen radicals produced by cytochrome P450 and the nicotinamide adenine dinucleotide phosphate complexes contribute to alcoholic liver damage. Alcohol feeding-induced expression and activation of cytochrome P450 and the nicotinamide adenine dinucleotide phosphate complex were prevented by TLR4-deficiency but not by MyD88-deficiency. Liver expression of interferon regulatory factor 3 (IRF3), a MyD88-independent signaling molecule, was not affected by chronic alcohol treatment in whole livers of WT mice or in any of the KO mice. However, the induction of IRF7, an IRF3-inducible gene, was found in Kupffer cells of alcohol-fed WT mice. Alcohol feeding also induced nuclear factor-kappaB activation in a TLR4-dependent MyD88-independent manner. CONCLUSION: While TLR4 deficiency was protective, MyD88 deficiency failed to prevent alcohol-induced liver damage and inflammation. These results suggest that the common TLR adapter, MyD88, is dispensable in TLR4-mediated liver injury in ALD.
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Global TLR4 deficiency in mice and gut sterilization with nonabsorbable antibiotics in rats reduce hepatic steatosis, oxidative stress and inflammation.
“Global TLR4 deficiency in mice as well as gut sterilization with nonabsorbable antibiotics in rats reduces hepatic steatosis, oxidative stress and inflammation46–48.”
From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [47]
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- Authors
- Hritz, I., Mandrekar, P., Velayudham, A., Catalano, D., Dolganiuc, A., Kodys, K., Kurt‐Jones, E., & Szabo, G.
- Affiliations
- University of Massachusetts Chan Medical School (US)
- Venue
- Hepatology
- Published
- 2008-10
- Volume
- 48
- Issue
- 4
- Pages
- 1224-1231
- ISSN
- 0270-9139 (ISSN-L)
- PMC
- PMC7137387
- OpenAlex
- W1988990189
- Cited by
- 415
- References
- 45
- Citations by year
- 2026: 17 · 2025: 11 · 2024: 16 · 2023: 25 · 2022: 19 · 2021: 22 · 2020: 22 · 2019: 13 · 2018: 23 · 2017: 25 · 2016: 29 · 2015: 36 · 2014: 27 · 2013: 27 · 2012: 31
- FWCI
- 17.02
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (AA 11576, R21AA014238, R01AA011576)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- TLR4, MyD88, alcoholic liver disease, MyD88-independent signaling, TLR2, IRF3, IRF7, NF-κB, Kupffer cells, liver inflammation, endotoxin, NADPH oxidase, cytochrome P450, hepatic steatosis, TLR4 knockout mice
- MeSH terms
- Ethanol, Animals, Disease Models, Animal, Fatty Liver, Liver, Liver Diseases, Alcoholic, Male, Mice, Inbred C57BL, NADP, Tumor Necrosis Factor-alpha, Signal Transduction, Interleukin-6, Reactive Oxygen Species, Mice, Knockout, Lipopolysaccharide Receptors, Cytochrome P-450 CYP2E1, Hepatocytes, Toll-Like Receptor 2, Toll-Like Receptor 4, Lymphocyte Antigen 96, Mice, Myeloid Differentiation Factor 88
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