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NOX4 regulates CCR2 and CCL2 mRNA stability in alcoholic liver disease
- Recruitment of inflammatory cells is a major feature of alcoholic liver injury however; the signals and cellular sources regulating this are not well defined. C-C chemokine receptor type 2 (CCR2) is expressed by active hepatic stellate cells (HSC) and is a key monocyte recruitment signal. Activated HSC are also important sources of hydrogen peroxide resulting from the activation of NADPH oxidase 4 (NOX4). As the role of this NOX in early alcoholic liver injury has not been addressed, we studied NOX4-mediated regulation of CCR2/CCL2 mRNA stability. NOX4 mRNA was significantly induced in patients with alcoholic liver injury, and was co-localized with αSMA-expressing activated HSC. We generated HSC-specific NOX4 KO mice and these were pair-fed on alcohol diet. Lipid peroxidation have not changed significantly however, the expression of CCR2, CCL2, Ly6C, TNFα, and IL-6 was significantly reduced in NOX4HSCKO compared to fl/fl mice. NOX4 promoter was induced in HSC by acetaldehyde treatment, and NOX4 has significantly increased mRNA half-life of CCR2 and CCL2 in conjunction with Ser221 phosphorylation and cytoplasmic shuttling of HuR. In conclusion, NOX4 is induced in early alcoholic liver injury and regulates CCR2/CCL2 mRNA stability thereby promoting recruitment of inflammatory cells and production of proinflammatory cytokines.
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| Author: | Yu Sasaki, Ali Dehnad, Sarah Fish, Ai Sato, Joy Jiang, Jijing Tian, Katrin SchröderORCiDGND, Ralf BrandesORCiDGND, Natalie J. Török |
|---|---|
| URN: | urn:nbn:de:hebis:30:3-485591 |
| DOI: | https://doi.org/10.1038/srep46144 |
| ISSN: | 2045-2322 |
| Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/28383062 |
| Parent Title (English): | Scientific reports |
| Publisher: | Macmillan Publishers Limited, part of Springer Nature |
| Place of publication: | [London] |
| Document Type: | Article |
| Language: | English |
| Year of Completion: | 2017 |
| Date of first Publication: | 2017/04/06 |
| Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
| Release Date: | 2018/12/20 |
| Tag: | Alcoholic liver disease; Mechanisms of disease |
| Volume: | 7 |
| Issue: | Art. 46144 |
| Page Number: | 9 |
| First Page: | 1 |
| Last Page: | 9 |
| Note: | Rights and permissions: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| HeBIS-PPN: | 446224081 |
| Institutes: | Medizin / Medizin |
| Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
| Sammlungen: | Universitätspublikationen |
| Licence (German): |  Creative Commons - Namensnennung 4.0 |
