Protein Thiol Redox Signaling in Monocytes and Macrophages

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][817][818][819][820][821][822][823][824][825][826][827][828][829][830][831][832][833][834][835]

Glutathionylation: a regulatory role of glutathione in physiological processes

“…It binds to other endogenous molecules forming, for example, the haemoglobin-glutathione complex, which serves as one of the markers of oxidative stress in human blood (7). With the advancement of detection methods in recent years (such as redox proteomic techniques and others), we have also learned about a vast number of interactions between glutathione and cellular proteins (8,9).…”

Mitogen-activated protein kinase phosphatase 1 (MKP-1) in macrophage biology and cardiovascular disease. A redox-regulated master controller of monocyte function and macrophage phenotype

“…We and others showed that maintaining protein thiol redox homeostasis is critical for the accurate programming and proper functioning of monocytes and macrophages [99, 103, 104]. Our data demonstrate that chronic exposure of monocytes to metabolic stress disrupts thiol redox homeostasis, resulting in monocyte dysfunction and the conversion of blood monocytes into a pro-inflammatory, pro-atherogenic phenotype, hyper-sensitive to chemoattractant [105, 106].…”

Quantification of Monocyte Chemotactic Activity In Vivo and Characterization of Blood Monocyte Derived Macrophages

“…Because the chemokine gradient we create in these mice is essentially unaffected by genetic, pharmacological, dietary or environmental exposure, changes in monocyte chemotactic activity actually reflect functional changes in these monocytes and, as we showed previously, also the reprogramming at both the protein and transcriptional level 17,20 . We reported that metabolic stress in mice increases monocyte responsiveness to chemoattractant and that this hyper-chemotactic activity correlates with increased protein S-glutathionylation, a reversible, redox-dependent posttranslational protein modification, which in most cases leads to loss of enzymatic and protein function 21,22 , and in some instances even promotes protein degradation 16,23 .…”