NOX4 Regulates CCR2 and CCL2 mRNA Stability in Alcoholic Liver Disease

Sci Rep. 2017 Apr 6;7:46144. 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 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetaldehyde / pharmacology
  • Alcohol Drinking / genetics
  • Animals
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Chemokine CCL2 / genetics*
  • Chemokine CCL2 / metabolism
  • ELAV-Like Protein 1 / metabolism
  • Hepatic Stellate Cells / drug effects
  • Hepatic Stellate Cells / metabolism
  • Humans
  • Inflammation Mediators / metabolism
  • Liver Diseases, Alcoholic / genetics*
  • Liver Diseases, Alcoholic / pathology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NADPH Oxidase 4 / metabolism*
  • Protein Transport / drug effects
  • RNA Stability / drug effects
  • RNA Stability / genetics*
  • Receptors, CCR2 / genetics*
  • Receptors, CCR2 / metabolism


  • Chemokine CCL2
  • ELAV-Like Protein 1
  • Inflammation Mediators
  • Receptors, CCR2
  • NADPH Oxidase 4
  • Acetaldehyde