title: Protein S-Glutathionylation Mediates Macrophage Responses to Metabolic Cues from the Extracellular Environment.
abstract: Protein S-glutathionylation, the formation of a mixed disulfide between glutathione and protein thiols, is an oxidative modification that has emerged as a new signaling paradigm, potentially linking oxidative stress to chronic inflammation associated with heart disease, diabetes, cancer, lung disease, and aging. Using a novel, highly sensitive, and selective proteomic approach to identify S-glutathionylated proteins, we tested the hypothesis that monocytes and macrophages sense changes in their microenvironment and respond to metabolic stress by altering their protein thiol S-glutathionylation status.
  
  
  
  We identified over 130 S-glutathionylated proteins, which were associated with a variety of cellular functions, including metabolism, transcription and translation, protein folding, free radical scavenging, cell motility, and cell death. Over 90% of S-glutathionylated proteins identified in metabolically stressed THP-1 monocytes were also found in hydrogen peroxide (H2O2)-treated cells, suggesting that H2O2mediates metabolic stress-induced protein S-glutathionylation in monocytes and macrophages. We validated our findings in mouse peritoneal macrophages isolated from both healthy and dyslipidemic atherosclerotic mice and found that 52% of the S-glutathionylated proteins found in THP-1 monocytes were also identified in vivo. Changes in macrophage protein S-glutathionylation induced by dyslipidemia were sexually dimorphic.
  
  
  
  We provide a novel mechanistic link between metabolic (and thiol oxidative) stress, macrophage dysfunction, and chronic inflammatory diseases associated with metabolic disorders.
  
  
  
  Our data support the concept that changes in the extracellular metabolic microenvironment induce S-glutathionylation of proteins central to macrophage metabolism and a wide array of cellular signaling pathways and functions, which in turn initiate and promote functional and phenotypic changes in macrophages. Antioxid. Redox Signal. 25, 836-851.
authors.affiliation: 1 Department of Kinesiology, Health, and Nutrition, University of Texas at San Antonio , San Antonio, Texas.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Ullevig
authors.affiliation: 2 Department of Molecular Medicine, College of Medicine, Inha University , Incheon, Korea.
authors.forename: Hong Seok
authors.initials: HS
authors.lastname: Kim
authors.affiliation: 3 Department of Pharmacology, University of Texas Health Science Center at San Antonio , San Antonio, Texas.
authors.forename: John D
authors.initials: JD
authors.lastname: Short
authors.affiliation: 4 Department of Radiology, University of Texas Health Science Center at San Antonio , San Antonio, Texas.
authors.forename: Sina
authors.initials: S
authors.lastname: Tavakoli
authors.affiliation: 5 Institutional Mass Spectrometry Core Laboratory, University of Texas Health Science Center at San Antonio , San Antonio, Texas.|6 Department of Biochemistry, University of Texas Health Science Center at San Antonio , San Antonio, Texas.
authors.forename: Susan T
authors.initials: ST
authors.lastname: Weintraub
authors.affiliation: 7 Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio , San Antonio, Texas.
authors.forename: Kevin
authors.initials: K
authors.lastname: Downs
authors.affiliation: 4 Department of Radiology, University of Texas Health Science Center at San Antonio , San Antonio, Texas.|6 Department of Biochemistry, University of Texas Health Science Center at San Antonio , San Antonio, Texas.|8 Department of Clinical Laboratory Sciences, University of Texas Health Science Center at San Antonio , San Antonio, Texas.
authors.forename: Reto
authors.initials: R
authors.lastname: Asmis
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D015415:Biomarkers; D002460:Cell Line; D019295:Computational Biology / Q000379:methods; D003463:Cues; D005110:Extracellular Space / Q000276:immunology / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D025941:Protein Interaction Mapping; D060066:Protein Interaction Maps; D011499:Protein Processing, Post-Translational; D013194:Staining and Labeling; D013312:Stress, Physiological / Q000235:genetics
chemical_list: D015415:Biomarkers; D006861:Hydrogen Peroxide; D005978:Glutathione
keywords: S-glutathionylation; atherosclerosis; macrophage; proteomics; thiols