NOX4 Regulates CCR2 and CCL2 mRNA Stability in Alcoholic Liver Disease View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2017-04-06

AUTHORS

Yu Sasaki, Ali Dehnad, Sarah Fish, Ai Sato, Joy Jiang, Jijing Tian, Kathrin Schröder, Ralf Brandes, Natalie J. Török

ABSTRACT

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. More... »

PAGES

46144

References to SciGraph publications

  • 2015-03-17. Alcoholic liver disease: mechanisms of injury and targeted treatment in NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY
  • 2014-02-25. Liver fibrosis and repair: immune regulation of wound healing in a solid organ in NATURE REVIEWS IMMUNOLOGY
  • 2001-02. HuR and mRNA stability in CELLULAR AND MOLECULAR LIFE SCIENCES
  • 2016-01-13. Immunology in the liver — from homeostasis to disease in NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY
  • 2008-06-26. Diverse molecular functions of Hu proteins in CELLULAR AND MOLECULAR LIFE SCIENCES
  • 2007-07. RNA regulons: coordination of post-transcriptional events in NATURE REVIEWS GENETICS
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/srep46144

    DOI

    http://dx.doi.org/10.1038/srep46144

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1084538188

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/28383062


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