title: Ablation of Glutaredoxin-1 Modulates House Dust Mite-Induced Allergic Airways Disease in Mice.
abstract: Protein S-glutathionylation (PSSG) is an oxidant-induced post-translational modification of protein cysteines that impacts structure and function. The oxidoreductase glutaredoxin-1 (Glrx1) under physiological conditions catalyzes deglutathionylation and restores the protein thiol group. The involvement of Glrx1/PSSG in allergic inflammation induced by asthma-relevant allergens remains unknown. In the present study, we examined the impact of genetic ablation of Glrx1 in the pathogenesis of house dust mite (HDM)-induced allergic airways disease in mice. Wild-type (WT) or Glrx1(-/-) mice were instilled intranasally with HDM on 5 consecutive days for 3 weeks. As expected, overall PSSG was increased in Glrx1(-/-) HDM mice as compared with WT animals. Total cells in bronchoalveolar lavage fluid were similarly increased in HDM-treated WT and Glrx1(-/-) mice. However, in response to HDM, mice lacking Glrx1 demonstrated significantly more neutrophils and macrophages but fewer eosinophils as compared with HDM-exposed WT mice. mRNA expression of the Th2-associated cytokines IL-13 and IL-6, as well as mucin-5AC (Muc5ac), was significantly attenuated in Glrx1(-/-) HDM-treated mice. Conversely, mRNA expression of IFN-γ and IL-17A was increased in Glrx1(-/-) HDM mice compared with WT littermates. Restimulation of single-cell suspensions isolated from lungs or spleens with HDM resulted in enhanced IL-17A and decreased IL-5 production in cells derived from inflamed Glrx1(-/-) mice compared with WT animals. Finally, HDM-induced tissue damping and elastance were significantly attenuated in Glrx1(-/-) mice compared with WT littermates. These results demonstrate that the Glrx1-PSSG axis plays a pivotal role in HDM-induced allergic airways disease in association with enhanced type 2 inflammation and restriction of IFN-γ and IL-17A.
authors.affiliation: Departments of 1 Pathology and Laboratory Medicine and.
authors.forename: Sidra M
authors.initials: SM
authors.lastname: Hoffman
authors.affiliation: Departments of 1 Pathology and Laboratory Medicine and.
authors.forename: Xi
authors.initials: X
authors.lastname: Qian
authors.affiliation: Departments of 1 Pathology and Laboratory Medicine and.
authors.forename: James D
authors.initials: JD
authors.lastname: Nolin
authors.affiliation: 2 Medicine, University of Vermont, Burlington, Vermont.
authors.forename: David G
authors.initials: DG
authors.lastname: Chapman
authors.affiliation: Departments of 1 Pathology and Laboratory Medicine and.
authors.forename: Shi Biao
authors.initials: SB
authors.lastname: Chia
authors.affiliation: Departments of 1 Pathology and Laboratory Medicine and.
authors.forename: Karolyn G
authors.initials: KG
authors.lastname: Lahue
authors.affiliation: Departments of 1 Pathology and Laboratory Medicine and.
authors.forename: Robert
authors.initials: R
authors.lastname: Schneider
authors.affiliation: 2 Medicine, University of Vermont, Burlington, Vermont.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Ather
authors.affiliation: 2 Medicine, University of Vermont, Burlington, Vermont.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Randall
authors.affiliation: Departments of 1 Pathology and Laboratory Medicine and.
authors.forename: David H
authors.initials: DH
authors.lastname: McMillan
authors.affiliation: Departments of 1 Pathology and Laboratory Medicine and.
authors.forename: Jane T
authors.initials: JT
authors.lastname: Jones
authors.affiliation: Departments of 1 Pathology and Laboratory Medicine and.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Taatjes
authors.affiliation: 2 Medicine, University of Vermont, Burlington, Vermont.
authors.forename: Minara
authors.initials: M
authors.lastname: Aliyeva
authors.affiliation: 2 Medicine, University of Vermont, Burlington, Vermont.
authors.forename: Nirav
authors.initials: N
authors.lastname: Daphtary
authors.affiliation: Departments of 1 Pathology and Laboratory Medicine and.
authors.forename: Sarah
authors.initials: S
authors.lastname: Abdalla
authors.affiliation: 2 Medicine, University of Vermont, Burlington, Vermont.
authors.forename: Lennart K A
authors.initials: LK
authors.lastname: Lundblad
authors.affiliation: 3 Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan; and.
authors.forename: Ye-Shih
authors.initials: YS
authors.lastname: Ho
authors.affiliation: Departments of 1 Pathology and Laboratory Medicine and.
authors.forename: Vikas
authors.initials: V
authors.lastname: Anathy
authors.affiliation: 2 Medicine, University of Vermont, Burlington, Vermont.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Irvin
authors.affiliation: 4 Department of Respiratory Medicine, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Emiel F M
authors.initials: EF
authors.lastname: Wouters
authors.affiliation: 4 Department of Respiratory Medicine, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Niki L
authors.initials: NL
authors.lastname: Reynaert
authors.affiliation: 2 Medicine, University of Vermont, Burlington, Vermont.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Dixon
authors.affiliation: Departments of 1 Pathology and Laboratory Medicine and.
authors.forename: Albert
authors.initials: A
authors.lastname: van der Vliet
authors.affiliation: 2 Medicine, University of Vermont, Burlington, Vermont.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Poynter
authors.affiliation: Departments of 1 Pathology and Laboratory Medicine and.
authors.forename: Yvonne M W
authors.initials: YM
authors.lastname: Janssen-Heininger
mesh_terms: D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D054477:Glutaredoxins / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006965:Hyperplasia; D006967:Hypersensitivity / Q000097:blood / Q000150:complications / Q000469:parasitology* / Q000473:pathology*; D007073:Immunoglobulin E / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D008168:Lung / Q000469:parasitology* / Q000473:pathology*; D008807:Mice, Inbred BALB C; D009093:Mucus / Q000378:metabolism; D011014:Pneumonia / Q000097:blood / Q000150:complications / Q000469:parasitology / Q000473:pathology; D039981:Pyroglyphidae / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012130:Respiratory Hypersensitivity / Q000097:blood / Q000469:parasitology / Q000473:pathology / Q000503:physiopathology; D015656:Respiratory Mechanics; D018418:Th2 Cells / Q000276:immunology
chemical_list: D016207:Cytokines; D054477:Glutaredoxins; D007074:Immunoglobulin G; D012333:RNA, Messenger; D007073:Immunoglobulin E; D005978:Glutathione
keywords: IFN-γ; IL-17A; asthma; neutrophils; protein S-glutathionylation