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

Hong Seok Kim, Sarah L. Ullevig, Debora Zamora, Chi Fung Lee, Reto Asmis

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

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 ofMKP-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, whereasMKP-1 overexpression blunted both MAPK activation and monocyte adhesion and migration induced by MCP-1.Metabolic stress promoted the Sglutathionylation of MKP-1, targetingMKP-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 inMKP-1 activity compared with nondiabetic mice. Hematopoietic MKP-1 deficiency in athero-sclerosis-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 ofMKP-1 activity is a critical step in monocyte priming and the metabolic stress-induced conversion of blood monocytes into a proatherogenic phenotype.

Original languageEnglish (US)
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number41
DOIs
StatePublished - Oct 9 2012

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Dual Specificity Phosphatase 1
Oxidation-Reduction
Mitogen-Activated Protein Kinase Phosphatases
Monocytes
Macrophages
Chemotaxis
Physiological Stress
Chemokine CCL2
Glutaredoxins
Chemotactic Factors
Sclerosis

Keywords

  • Cell adhesion
  • Cell migration
  • Inflammation
  • Metabolic diseases

ASJC Scopus subject areas

  • General

Cite this

Redox regulation of MAPK phosphatase 1 controls monocyte migration and macrophage recruitment. / Kim, Hong Seok; Ullevig, Sarah L.; Zamora, Debora; Lee, Chi Fung; Asmis, Reto.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 41, 09.10.2012.

Research output: Contribution to journalArticle

Kim, Hong Seok ; Ullevig, Sarah L. ; Zamora, Debora ; Lee, Chi Fung ; Asmis, Reto. / Redox regulation of MAPK phosphatase 1 controls monocyte migration and macrophage recruitment. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 41.
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abstract = "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 ofMKP-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, whereasMKP-1 overexpression blunted both MAPK activation and monocyte adhesion and migration induced by MCP-1.Metabolic stress promoted the Sglutathionylation of MKP-1, targetingMKP-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 inMKP-1 activity compared with nondiabetic mice. Hematopoietic MKP-1 deficiency in athero-sclerosis-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 ofMKP-1 activity is a critical step in monocyte priming and the metabolic stress-induced conversion of blood monocytes into a proatherogenic phenotype.",
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