title: Disruption of the transcription factor Nrf2 promotes pro-oxidative dendritic cells that stimulate Th2-like immunoresponsiveness upon activation by ambient particulate matter.
abstract: Oxidative stress is important in dendritic cell (DC) activation. Environmental particulate matter (PM) directs pro-oxidant activities that may alter DC function. Nuclear erythroid 2 p45-related factor 2 (Nrf2) is a redox-sensitive transcription factor that regulates expression of antioxidant and detoxification genes. Oxidative stress and defective antioxidant responses may contribute to the exacerbations of asthma. We hypothesized that PM would impart differential responses by Nrf2 wild-type DCs as compared with Nrf2(-/-) DCs. We found that the deletion of Nrf2 affected important constitutive functions of both bone marrow-derived and highly purified myeloid lung DCs such as the secretion of inflammatory cytokines and their ability to take up exogenous Ag. Stimulation of Nrf2(-/-) DCs with PM augmented oxidative stress and cytokine production as compared with resting or Nrf2(+/+) DCs. This was associated with the enhanced induction of Nrf2-regulated antioxidant genes. In contrast to Nrf2(+/+) DCs, coincubation of Nrf2(-/-) DCs with PM and the antioxidant N-acetyl cysteine attenuated PM-induced up-regulation of CD80 and CD86. Our studies indicate a previously underappreciated role of Nrf2 in innate immunity and suggest that deficiency in Nrf2-dependent pathways may be involved in susceptibility to the adverse health effects of air pollution in part by promoting Th2 cytokine responses in the absence of functional Nrf2. Moreover, our studies have uncovered a hierarchal response to oxidative stress in terms of costimulatory molecule expression and cytokine secretion in DCs and suggest an important role of heightened oxidative stress in proallergic Th2-mediated immune responses orchestrated by DCs.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA. marc_williams@urmc.rochester.edu
authors.forename: Marc A
authors.initials: MA
authors.lastname: Williams
authors.forename: Tirumalai
authors.initials: T
authors.lastname: Rangasamy
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Bauer
authors.forename: Smruti
authors.initials: S
authors.lastname: Killedar
authors.forename: Matthew
authors.initials: M
authors.lastname: Karp
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Kensler
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Patrick
authors.initials: P
authors.lastname: Breysse
authors.forename: Shyam
authors.initials: S
authors.lastname: Biswal
authors.forename: Steve N
authors.initials: SN
authors.lastname: Georas
mesh_terms: D000818:Animals; D015142:Baltimore; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D018384:Oxidative Stress / Q000187:drug effects / Q000276:immunology*; D052638:Particulate Matter / Q000633:toxicity*; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
chemical_list: D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D052638:Particulate Matter
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