Regulation of Monocyte Adhesion and Migration by Nox4

被引:25
作者
Lee, Chi Fung [1 ]
Ullevig, Sarah [1 ]
Kim, Hong Seok [2 ]
Asmis, Reto [1 ,2 ]
机构
[1] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, Sch Hlth Profess, San Antonio, TX 78229 USA
[2] Univ Texas Hlth Sci Ctr San Antonio, Dept Clin Lab Sci, Sch Hlth Profess, San Antonio, TX 78229 USA
来源
PLOS ONE | 2013年 / 8卷 / 06期
关键词
REDOX REGULATION; MITOCHONDRIAL DYSFUNCTION; GLUTATHIONE-REDUCTASE; TYROSINE-PHOSPHATASE; SIGNAL-TRANSDUCTION; HUMAN MACROPHAGES; CELL-MIGRATION; BETA-ACTIN; KINASE; SUPEROXIDE;
D O I
10.1371/journal.pone.0066964
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
We showed that metabolic disorders promote thiol oxidative stress in monocytes, priming monocytes for accelerated chemokine-induced recruitment, and accumulation at sites of vascular injury and the progression of atherosclerosis. The aim of this study was to identify both the source of reactive oxygen species (ROS) responsible for thiol oxidation in primed and dysfunctional monocytes and the molecular mechanisms through which ROS accelerate the migration and recruitment of monocyte-derived macrophages. We found that Nox4, a recently identified NADPH oxidase in monocytes and macrophages, localized to focal adhesions and the actin cytoskeleton, and associated with phospho-FAK, paxillin, and actin, implicating Nox4 in the regulation of monocyte adhesion and migration. We also identified Nox4 as a new, metabolic stress-inducible source of ROS that controls actin S-glutathionylation and turnover in monocytes and macrophages, providing a novel mechanistic link between Nox4-derived H2O2 and monocyte adhesion and migration. Actin associated with Nox4 was S-glutathionylated, and Nox4 association with actin was enhanced in metabolically-stressed monocytes. Metabolic stress induced Nox4 and accelerated monocyte adhesion and chemotaxis in a Nox4-dependent mechanism. In conclusion, our data suggest that monocytic Nox4 is a central regulator of actin dynamics, and induction of Nox4 is the rate-limiting step in metabolic stress-induced monocyte priming and dysfunction associated with accelerated atherosclerosis and the progression of atherosclerotic plaques.
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页数:9
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