NOX4 Regulates CCR2 and CCL2 mRNA Stability in Alcoholic Liver Disease

Yu Sasaki, Ali Dehnad, Sarah Fish, Ai Sato, Xiaosong Jiang, Jijing Tian, Kathrin Schröder, Ralf Brandes, Natalia J Torok

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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 NOX4 HSCKO 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.

Original languageEnglish (US)
Article number46144
JournalScientific Reports
Volume7
DOIs
StatePublished - Apr 6 2017

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    Sasaki, Y., Dehnad, A., Fish, S., Sato, A., Jiang, X., Tian, J., Schröder, K., Brandes, R., & Torok, N. J. (2017). NOX4 Regulates CCR2 and CCL2 mRNA Stability in Alcoholic Liver Disease. Scientific Reports, 7, [46144]. https://doi.org/10.1038/srep46144