NADPH Oxidase 4 Mediates Monocyte Priming and Accelerated Chemotaxis Induced by Metabolic Stress

Ullevig, Sarah L.; Zhao, Qiu; Lee, Chi Fung; Kim, Hong Seok; Zamora, Debora A.; Asmis, Reto

doi:10.1161/atvbaha.111.238899

Cited by 67 publications

(143 citation statements)

References 62 publications

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“…We showed that in mice the chemotactic activity of monocytes increases with rising levels of hyperglycemia and hyperlipidemia and is associated with increased macrophage recruitment and accelerated atherosclerotic lesion formation (18). We further demonstrated that metabolic stress induces the expression of Nox4, an inducible Nox family member that we identified in monocytes and macrophages (19) and which plays a critical role in monocyte priming by metabolic stress (17). The aim of this study was to elucidate the mechanisms underlying the conversion of monocytes into this hypermigratory, proatherogenic phenotype induced by metabolic stress and to identify the redoxsensitive pathways targeted by Nox4-derived ROS in primed monocytes.…”

Section: Discussionmentioning

confidence: 64%

“…MKPs are sensitive to inactivation via the reversible oxidation of their active-site cysteine (32). We showed that in monocytes metabolic stress promotes protein S-glutathionylation, i.e., the formation of mixed disulfides between GSH and reactive protein thiols (17,18); however, Sglutathionylation of MKPs had not been reported. To identify the mechanism by which metabolic stress promotes the inactivation and loss of MKP-1 in monocytes and to explore whether MKP-1 is S-glutathionylated in metabolically primed monocytes, we preloaded THP-1 monocytes with biotin-labeled glutathione and performed streptavidin-bead pulldown experiments.…”

Section: Metabolic Stress Promotes S-glutathionylation and Subsequentmentioning

confidence: 91%

“…S4) therefore may be an underestimation of total MKP-1 degradation triggered by metabolic stress. Increasing Grx1 activity also protected monocytes from converting into the hyperadhesive ( Metabolic stress in monocytes induces Nox4 (17), an inducible NADPH oxidase (Nox) family member we identified in monocytes and macrophages (19), and thereby promotes the S-glutathionylation of actin (17). To examine whether Nox4-derived ROS also mediate the S-glutathionylation, inactivation, and degradation of MKP-1, THP-1 monocytes were transfected with siRNA directed against Nox4 and then were exposed to metabolic stress, i.e., LDL plus high glucose.…”

Section: Metabolic Stress Promotes S-glutathionylation and Subsequentmentioning

confidence: 98%

“…In dyslipidemic and in diabetic mice the increased responsiveness of monocytes to chemokine-induced migration correlated with the level of intracellular thiol oxidative stress and was a strong predictor of both lesion size and macrophage content of atherosclerotic plaques (17,18). Monocyte priming by metabolic stress is mediated by the induction of Nox4, an NADPH oxidase recently identified in monocytes and macrophages (19).…”

mentioning

confidence: 98%

“…Our recent studies explored this possibility, and we showed that metabolic stress primes monocytes for activation by chemoattractants, including monocyte chemoattractant protein-1 (MCP-1, also known as "CCL2," "SCYA2," and "MCAF"), a major chemoattractant involved in the recruitment of macrophages into atherosclerotic lesions (14)(15)(16), transforming these cells into a hypermigratory, proinflammatory phenotype (17,18). In dyslipidemic and in diabetic mice the increased responsiveness of monocytes to chemokine-induced migration correlated with the level of intracellular thiol oxidative stress and was a strong predictor of both lesion size and macrophage content of atherosclerotic plaques (17,18).…”

mentioning

confidence: 99%

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Redox regulation of MAPK phosphatase 1 controls monocyte migration and macrophage recruitment

Kim¹,

Ullevig

Zamora³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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104

125

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Monocytic adhesion and chemotaxis are regulated by MAPK pathways, which in turn are controlled by redox-sensitive MAPK phosphatases (MKPs). We recently reported that metabolic disorders prime monocytes for enhanced recruitment into vascular lesions by increasing monocytes' responsiveness to chemoattractants. However, the molecular details of this proatherogenic mechanism were not known. Here we show that monocyte priming results in the S-glutathionylation and subsequent inactivation and degradation of MKP-1. Chronic exposure of human THP-1 monocytes to diabetic conditions resulted in the loss of MKP-1 protein levels, the hyperactivation of ERK and p38 in response to monocyte chemoattractant protein-1 (MCP-1), and increased monocyte adhesion and chemotaxis. Knockdown of MKP-1 mimicked the priming effects of metabolic stress, whereas MKP-1 overexpression blunted both MAPK activation and monocyte adhesion and migration induced by MCP-1. Metabolic stress promoted the Sglutathionylation of MKP-1, targeting MKP-1 for proteasomal degradation. Preventing MKP-1 S-glutathionylation in metabolically stressed monocytes by overexpressing glutaredoxin 1 protected MKP-1 from degradation and normalized monocyte adhesion and chemotaxis in response to MCP-1. Blood monocytes isolated from diabetic mice showed a 55% reduction in MKP-1 activity compared with nondiabetic mice. Hematopoietic MKP-1 deficiency in atherosclerosis-prone mice mimicked monocyte priming and dysfunction associated with metabolic disorders, increased monocyte chemotaxis in vivo, and accelerated atherosclerotic lesion formation. In conclusion, we identified MKP-1 as a central redox-sensitive regulator of monocyte adhesion and migration and showed that the loss of MKP-1 activity is a critical step in monocyte priming and the metabolic stress-induced conversion of blood monocytes into a proatherogenic phenotype.M etabolic disorders such as obesity and diabetes are associated with a state of chronic, low-grade inflammation (1, 2), which appears to contribute to the development of micro-and macrovascular complications such as atherosclerosis, nephropathy, and retinopathy (3-5). The cellular and molecular mechanisms involved in chronic inflammation associated with metabolic disorders are not yet fully understood, but the recruitment of blood monocytes to sites of vascular injury appears to play a central and rate-limiting role in all these complications. Metabolic disorders impact blood vessels at multiple levels, including lipid depositions, endothelial injury, and smooth muscle cell proliferation and migration, which individually or in concert initiate monocyte recruitment and promote vascular inflammation (6, 7). However, metabolic disorders also appear to affect blood monocytes directly. A number of studies reported that monocytes both in patients with metabolic disorders and in dyslipidemic or diabetic mice undergo phenotypical and functional changes that may contribute directly to the development and progression of chronic inflammatory vascular diseases (8-13)...

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Section: Discussionmentioning

confidence: 64%

Section: Metabolic Stress Promotes S-glutathionylation and Subsequentmentioning

confidence: 91%

Section: Metabolic Stress Promotes S-glutathionylation and Subsequentmentioning

confidence: 98%

mentioning

confidence: 98%

mentioning

confidence: 99%

See 3 more Smart Citations

Redox regulation of MAPK phosphatase 1 controls monocyte migration and macrophage recruitment

Kim¹,

Ullevig

Zamora³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

104

125

View full text Add to dashboard Cite

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Actin filaments—A target for redox regulation

et al. 2016

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Actin and its ability to polymerize into dynamic filaments is critical for the form and function of cells throughout the body. While multiple proteins have been characterized as affecting actin dynamics through non-covalent means, actin and its protein regulators are also susceptible to covalent modifications of their amino acid residues. In this regard, oxidation-reduction (Redox) intermediates have emerged as key modulators of the actin cytoskeleton with multiple different effects on cellular form and function. Here, we review work implicating Redox intermediates in post-translationally altering actin and discuss what is known regarding how these alterations affect the properties of actin. We also focus on two of the best characterized enzymatic sources of these Redox intermediates – the NADPH oxidase NOX and the flavoprotein monooxygenase MICAL – and detail how they have both been identified as altering actin, but share little similarity and employ different means to regulate actin dynamics. Finally, we discuss the role of these enzymes and redox signaling in regulating the actin cytoskeleton in vivo and highlight their importance for neuronal form and function in health and disease.

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Metabolic regulation of leukocyte motility and migration

Marelli‐Berg

Jangani

2018

Journal of Leukocyte Biology

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Dynamic reorganization of the cytoskeleton is essential for numerous cellular processes including leukocyte migration. This process presents a substantial bioenergetic challenge to migrating cells as actin polymerization is dependent on ATP hydrolysis. Hence, migrating cells must increase ATP production to meet the increased metabolic demands of cytoskeletal reorganization. Despite this long-standing evidence, the metabolic regulation of leukocyte motility and trafficking has only recently begun to be investigated. In this review, we will summarize current knowledge of the crosstalk between cell metabolism and the cytoskeleton in leukocytes, and discuss the concept that leukocyte metabolism may reprogram in response to migratory stimuli and the different environmental cues received during recirculation ultimately regulating leukocyte motility and migration.

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NADPH Oxidase 4 Mediates Monocyte Priming and Accelerated Chemotaxis Induced by Metabolic Stress

Cited by 67 publications

References 62 publications

Redox regulation of MAPK phosphatase 1 controls monocyte migration and macrophage recruitment

Redox regulation of MAPK phosphatase 1 controls monocyte migration and macrophage recruitment

Actin filaments—A target for redox regulation

Metabolic regulation of leukocyte motility and migration

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