Regulation of Monocyte Adhesion and Migration by Nox4

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.

Poldip2 controls vascular smooth muscle cell migration by regulating focal adhesion turnover and force polarization

“…Multiple previous studies have shown that changes in the intracellular ROS concentration can severely affect the fate of focal adhesions (10,16,17,25,37). ROS scavengers such as N-acetyl cysteine and flavin oxidase inhibitors such as diphenyleneiodonium can cause dissolution of focal adhesions, whereas intracellular increases in H 2 O 2 can activate FAK and consequently stimulate cell adhesion and spreading.…”

β-elemene inhibits monocyte–endothelial cells interactions via reactive oxygen species/MAPK/NF-κB signaling pathway in vitro

“…The recruitment of circulating monocytes to the sites of arterial injuries and adhere to endothelium and transmigrate into the arterial wall are an initial step of the progression of atherosclerosis (Clapp et al, 2004;Erdogan et al, 2007;Lee et al, 2013;Mestas and Ley, 2008).…”

Protein Thiol Redox Signaling in Monocytes and Macrophages

“…To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars primes monocytes into a hypermigratory and proatherogenic phenotype, which is dependent on the induction of NOX4-mediated H 2 O 2 production (207). This priming effect is associated with S-glutathionylation of several proteins, including actin (115,116), MKP-1 (101), and 14-3-3f (100), which appear to accelerate monocyte chemotaxis via increasing actin remodeling (207). Prevention of protein-Sglutathionylation by transgenic overexpression of cytoplasmic Grx is sufficient to eliminate the metabolic stress-induced priming effect in monocytes (207).…”

“…Several reports suggest that NOX4 is also expressed in both human and murine myeloid cells (78,115,116) (207). NOX4 is also detectable by RT-PCR in mouse bone marrow-derived macrophages and in murine thioglycollate-elicited peritoneal macrophages (data unpublished).…”