NOX4 Regulates CCR2 and CCL2 mRNA Stability in Alcoholic Liver Disease

作者：Sasaki Yu; Dehnad Ali; Fish Sarah; Sato Ai; Jiang Joy; Tian Jijing; Schroeder Kathrin; Brandes Ralf; Torok Natalie J^*

来源：Scientific Reports, 2017, 7(1): 46144.

DOI：10.1038/srep46144

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 aSMA-expressing activated HSC. We generated HSCspecific NOX4 KO mice and these were pair-fed on alcohol diet. Lipid peroxidation have not changed significantly however, the expression of CCR2, CCL2, Ly6C, TNF alpha, 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.

• 出版日期2017-4-6