title: Ablation of the Thiol Transferase Glutaredoxin-1 Augments Protein S-Glutathionylation and Modulates Type 2 Inflammatory Responses and IL-17 in a House Dust Mite Model of Allergic Airway Disease in Mice.
abstract: S-glutathionylation has emerged as an oxidant-induced post-translational modification of protein cysteines that affects structure and function. The oxidoreductase glutaredoxin-1 (Glrx1), under physiological conditions, catalyzes deglutathionylation and restores the protein thiol group. The involvement of Grx1/S-glutathionylation in allergic inflammation induced by asthma-relevant allergens remains unknown. In the present study we examined the impact of genetic ablation of Glrx1 for the pathogenesis of house dust mite (HDM)-induced allergic airway disease in mice. Wild-type (WT) or Glrx1(-/-) mice in the BALB/c background were instilled intranasally with 50 μg of HDM 5 consecutive days for 3 weeks and killed 72 hours post final exposure. As expected, overall protein S-glutathionylation was increased in Glrx1(-/-) mice exposed to HDM as compared with WT animals. Total cells in the bronchoalveolar lavage fluid were similarly increased in WT and Glrx1(-/-) HDM-treated mice compared with phosphate-buffered saline-treated control mice. However, in response to HDM, mice lacking Glrx1 demonstrated significantly more neutrophils but fewer eosinophils than HDM-exposed WT mice. mRNA expression of the Th2-associated cytokine IL-13, as well as MUC5ac, was significantly attenuated in Glrx1(-/-) HDM-treated mice compared with WT mice. Conversely, expression of IL-17A was increased in Glrx1(-/-) HDM mice compared with WT mice. Last, HDM-induced tissue damping and elastance were significantly attenuated in Glrx1(-/-) mice compared with WT littermates. These results demonstrate that the Grx1/S-glutathionylation redox status plays a pivotal role in HDM-induced allergic inflammation and airway hyperresponsiveness and suggest a potential role of Glrx1/S-glutathionylation in controlling the nature of the HDM-induced adaptive immune responses by promoting Type-2-driven inflammation and restricting IL-17A.
authors.affiliation: 1 Department of Pathology and Laboratory Medicine, and.
authors.forename: Sidra M
authors.initials: SM
authors.lastname: Hoffman
authors.affiliation: 1 Department of Pathology and Laboratory Medicine, and.
authors.forename: James D
authors.initials: JD
authors.lastname: Nolin
authors.affiliation: 1 Department of Pathology and Laboratory Medicine, and.
authors.forename: Jane T
authors.initials: JT
authors.lastname: Jones
authors.affiliation: 1 Department of Pathology and Laboratory Medicine, and.
authors.forename: Karolyn G
authors.initials: KG
authors.lastname: Lahue
authors.affiliation: 2 Department of Medicine, The University of Vermont, Burlington, Vermont.
authors.forename: David G
authors.initials: DG
authors.lastname: Chapman
authors.affiliation: 1 Department of Pathology and Laboratory Medicine, and.
authors.forename: Minara
authors.initials: M
authors.lastname: Aliyeva
authors.affiliation: 2 Department of Medicine, The University of Vermont, Burlington, Vermont.
authors.forename: Nirav
authors.initials: N
authors.lastname: Daphtary
authors.affiliation: 2 Department of Medicine, The University of Vermont, Burlington, Vermont.
authors.forename: Lennart K A
authors.initials: LK
authors.lastname: Lundblad
authors.affiliation: 1 Department of Pathology and Laboratory Medicine, and.
authors.forename: Sarah
authors.initials: S
authors.lastname: Abdalla
authors.affiliation: 2 Department of Medicine, The University of Vermont, Burlington, Vermont.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Ather
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: 2 Department of Medicine, The University of Vermont, Burlington, Vermont.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Irvin
authors.affiliation: 1 Department of Pathology and Laboratory Medicine, and.
authors.forename: Vikas
authors.initials: V
authors.lastname: Anathy
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: 2 Department of Medicine, The University of Vermont, Burlington, Vermont.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Poynter
authors.affiliation: 1 Department of Pathology and Laboratory Medicine, and.
authors.forename: Yvonne M W
authors.initials: YM
authors.lastname: Janssen-Heininger