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Review
. 2016 Nov 20;25(15):816-835.
doi: 10.1089/ars.2016.6697. Epub 2016 Jul 13.

Protein Thiol Redox Signaling in Monocytes and Macrophages

John D Short  1 , Kevin Downs  2 , Sina Tavakoli  3 , Reto Asmis  4   5
Affiliations
Review

Protein Thiol Redox Signaling in Monocytes and Macrophages

John D Short et al. Antioxid Redox Signal. .

Abstract

Significance: Monocyte and macrophage dysfunction plays a critical role in a wide range of inflammatory disease processes, including obesity, impaired wound healing diabetic complications, and atherosclerosis. Emerging evidence suggests that the earliest events in monocyte or macrophage dysregulation include elevated reactive oxygen species production, thiol modifications, and disruption of redox-sensitive signaling pathways. This review focuses on the current state of research in thiol redox signaling in monocytes and macrophages, including (i) the molecular mechanisms by which reversible protein-S-glutathionylation occurs, (ii) the identification of bona fide S-glutathionylated proteins that occur under physiological conditions, and (iii) how disruptions of thiol redox signaling affect monocyte and macrophage functions and contribute to atherosclerosis. Recent Advances: Recent advances in redox biochemistry and biology as well as redox proteomic techniques have led to the identification of many new thiol redox-regulated proteins and pathways. In addition, major advances have been made in expanding the list of S-glutathionylated proteins and assessing the role that protein-S-glutathionylation and S-glutathionylation-regulating enzymes play in monocyte and macrophage functions, including monocyte transmigration, macrophage polarization, foam cell formation, and macrophage cell death.

Critical issues: Protein-S-glutathionylation/deglutathionylation in monocytes and macrophages has emerged as a new and important signaling paradigm, which provides a molecular basis for the well-established relationship between metabolic disorders, oxidative stress, and cardiovascular diseases.

Future directions: The identification of specific S-glutathionylated proteins as well as the mechanisms that control this post-translational protein modification in monocytes and macrophages will facilitate the development of new preventive and therapeutic strategies to combat atherosclerosis and other metabolic diseases. Antioxid. Redox Signal. 25, 816-835.

Keywords: S-glutathionylation; atherosclerosis; macrophage; redox signaling; thiols.

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Figures

<b>FIG. 1.</b>
FIG. 1.
Biochemical mechanisms for reversible S-glutathionylation of protein thiols. There are four major mechanisms by which protein thiols can become S-glutathionylated: (1) in the presence of hydrogen peroxide (H2O2), protein thiols are oxidized to highly reactive protein sulfenic acids that can react with the glutathione (GSH); (2) several lines of evidence support a thiyl radical-mediated mechanism for protein-S-glutathionylation, which involves a protein thiyl radical (protein-S·) reacting with GSH and being stabilized by radical transfer to molecular oxygen to form superoxide (O2−•); (3) cellular GSH can react with endogenous reactive oxygen species (ROS) to form a GSH sulfenic acid, thereby facilitating a reaction with a reduced protein thiol; and (4) GSH exchange occurs between glutathione disulfide (GSSG) and a protein thiolate, generating an S-glutathionylated protein and GSH. Protein-S-glutathionylation is reversed by the activity of glutaredoxin (Grx) enzymes. Deglutathionylation and reduction of a target protein involve the transfer of the glutathionyl group onto Grx, which can subsequently be reduced by GSH, resulting in the formation of GSSG. In turn, GSSG is reduced back to two molecules of GSH by glutathione reductase (GR), which uses electrons from NADPH. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
<b>FIG. 2.</b>
FIG. 2.
Proteins regulated by both protein-S-glutathionylation and protein phosphorylation. The reversible nature of protein-S-glutathionylation resembles the process of protein phosphorylation. The forward mechanism of protein phosphorylation is driven by kinases, whereas the exact mechanism of protein-S-glutathionylation in intact cells and tissues is not yet fully understood (?). Depending on the system, protein-S-glutathionylation appears to be driven by either nonenzymatic or enzymatic mechanisms. The reversal of phosphorylation is mediated by phosphatase enzymes, whereas S-glutathionylation is reversed by Grx enzymes. In addition, both of these modifications have been reported to alter the activity of the proteins (examples are listed: Target), although via modification of discrete amino acids. *Phosphorylation and glutathionylation of actin result in changes in polymerization state, as opposed to changes in enzymatic activity for the other protein targets. +Proteins for which S-glutathionylation has been reported in monocytes and/or macrophages. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
<b>FIG. 3.</b>
FIG. 3.
Mechanisms and consequences of protein-S-glutathionylation in monocytes and macrophages. Both activation by cytokines or chemokines and metabolic stress can result in increased intracellular H2O2 production, which is a product of mitochondria and ROS-generating enzymes. Increased H2O2 production can lead to increased protein-S-glutathionylation in monocytes and macrophages. Alternatively, altered protein-S-glutathionylation has been reported to be mediated by glutathione S-transferase (GST) enzymes in these cell types. Cytokine, chemokine, and metabolic stress-induced protein-S-glutathionylation can be prevented either by the activity of antioxidant enzymes at the level of ROS scavenging or reversed by Grx-mediated deglutathionylation. As a consequence of protein-S-glutathionylation, changes in protein activity, function, and/or localization can lead to monocyte and macrophage dysfunction. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
<b>FIG. 4.</b>
FIG. 4.
Metabolic stress enhances monocyte adhesion and recruitment via S-glutathionylation of mitogen-activated protein kinase phosphatase 1 (MKP-1). Metabolic stress induces H2O2-mediated S-glutathionylation of MKP-1, resulting in MKP-1 inactivation and degradation. As a result, hyperactivation (increased phosphorylation) of both ERK and p38MAPK signaling occurs, which leads to enhanced monocyte adhesion and chemotaxis, respectively. These metabolic stress-induced changes in protein signaling and monocyte migration can be reversed by increased Grx1 expression. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
<b>FIG. 5.</b>
FIG. 5.
Contribution of protein thiol oxidative stress in monocytes and macrophages to atherogenesis. Development of atherosclerosis is complex and requires monocytes and macrophages at several steps during the pathophysiological process. Upon vascular injury, monocytes adhere to endothelial cells and transmigrate into the intima. Upon entering the subintimal space, monocytes differentiate into macrophages. Activation of macrophages (M0) results in their polarization into either a proinflammatory (M1) or inflammation-resolving (M2) phenotype. Uptake of modified LDL transforms macrophages into lipid-laden foam cells. Ultimately, these foam cells undergo cell death, which exacerbates plaque progression and destabilization. Conditions that promote protein thiol oxidative stress in monocytes have been previously reported to affect chemokine-induced adhesion and migration, processes that control macrophage infiltration into sites of vascular injury and drive atherogenesis and plaque progression. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
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References

    1. Adachi T, Weisbrod RM, Pimentel DR, Ying J, Sharov VS, Schoneich C, and Cohen RA. S-Glutathiolation by peroxynitrite activates SERCA during arterial relaxation by nitric oxide. Nat Med 10: 1200–1207, 2004 - PubMed
    1. Aesif SW, Anathy V, Kuipers I, Guala AS, Reiss JN, Ho YS, and Janssen-Heininger YM. Ablation of glutaredoxin-1 attenuates lipopolysaccharide-induced lung inflammation and alveolar macrophage activation. Am J Respir Cell Mol Biol 44: 491–499, 2011 - PMC - PubMed
    1. Aesif SW, Janssen-Heininger YM, and Reynaert NL. Protocols for the detection of s-glutathionylated and s-nitrosylated proteins in situ. Methods Enzymol 474: 289–296, 2010 - PMC - PubMed
    1. Aesif SW, Kuipers I, van der Velden J, Tully JE, Guala AS, Anathy V, Sheely JI, Reynaert NL, Wouters EF, van der Vliet A, and Janssen-Heininger YM. Activation of the glutaredoxin-1 gene by nuclear factor kappaB enhances signaling. Free Radic Biol Med 51: 1249–1257, 2011 - PMC - PubMed
    1. Allen EM. and Mieyal JJ. Protein-thiol oxidation and cell death: regulatory role of glutaredoxins. Antioxid Redox Signal 17: 1748–1763, 2012 - PMC - PubMed

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