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

Research output: Contribution to journalArticle

3 Citations (Scopus)

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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CC Chemokines
Alcoholic Liver Diseases
Chemokine CCL2
Chemokine Receptors
NADPH Oxidase
RNA Stability
Hepatic Stellate Cells
Liver
Wounds and Injuries
Messenger RNA
Hydrogen Peroxide
Lipid Peroxidation
Half-Life
Monocytes
Interleukin-6
Phosphorylation
Alcohols
Cytokines
Diet

ASJC Scopus subject areas

  • General

Cite this

NOX4 Regulates CCR2 and CCL2 mRNA Stability in Alcoholic Liver Disease. / Sasaki, Yu; Dehnad, Ali; Fish, Sarah; Sato, Ai; Jiang, Xiaosong; Tian, Jijing; Schröder, Kathrin; Brandes, Ralf; Torok, Natalia J.

In: Scientific Reports, Vol. 7, 46144, 06.04.2017.

Research output: Contribution to journalArticle

Sasaki, Y, Dehnad, A, Fish, S, Sato, A, Jiang, X, Tian, J, Schröder, K, Brandes, R & Torok, NJ 2017, 'NOX4 Regulates CCR2 and CCL2 mRNA Stability in Alcoholic Liver Disease', Scientific Reports, vol. 7, 46144. https://doi.org/10.1038/srep46144
Sasaki, Yu ; Dehnad, Ali ; Fish, Sarah ; Sato, Ai ; Jiang, Xiaosong ; Tian, Jijing ; Schröder, Kathrin ; Brandes, Ralf ; Torok, Natalia J. / NOX4 Regulates CCR2 and CCL2 mRNA Stability in Alcoholic Liver Disease. In: Scientific Reports. 2017 ; Vol. 7.
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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.",
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