Abstract
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.
Highlights
Atherosclerosis like other chronic inflammatory diseases is closely associated with systemic oxidative stress [1,2]
To examine whether Nox4 is present in focal adhesions of macrophages, we performed immunofluorescence studies in adherent human monocyte-derived macrophages (HMDM) stained with antibodies directed against paxillin, a focal adhesion protein that serves as a docking protein for cytoskeletal protein and kinases, including focal adhesion kinase (FAK) [21], and against the activated form of FAK, i.e. FAK phosphorylated at tyrosine-397 (FAK-Y397Pi) [22], a marker of activated focal adhesions
Monocyte recruitment is involved in chronic inflammatory diseases and is the rate limiting step for the development atherosclerosis
Summary
Atherosclerosis like other chronic inflammatory diseases is closely associated with systemic oxidative stress [1,2]. The origins of the reactive oxygen species (ROS) that contribute to systemic oxidative stress are not clear since ROS can be generated by multiple different sources, including mitochondria or as byproducts of numerous enzymatic reactions involving cytochrome P450 enzymes and 5-lipoxygenase, and resulting from the uncoupling of nitric oxide synthases [3]. For cellular redox signaling to be specific and effective and to avoid nonspecific oxidation, it is essential that ROS are generated in close proximity of their redox-sensitive targets [6,7]. This is achieved by NADPH oxidases (Nox), professional ROS producers [8]. We identified Nox in monocytes and macrophages as a source of intracellular ROS involved in macrophage death [14]. We showed that metabolic stress primes monocytes for activation by chemokines and that the transformation of monocytes into this hyperresponsive phenotype increases monocyte motility and requires the induction of Nox and increased H2O2 production [15]
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