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* Division of Pulmonary and Critical Care Medicine and
Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642;
Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, and
Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205; and
¶ Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Japan
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.
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1 This research was supported in part by a New Investigator Project from the Center for Childhood Asthma in the Urban Environment (funded by National Institute of Environmental Health Sciences (NIEHS) and U.S. Environmental Protection Agency Grant P01ES09606 to S.N.G. and M.A.W.) as well as by the Department of Medicine, University of Rochester School of Medicine and Dentistry (Rochester, NY). The research was also supported by National Institutes of Health (NIH) Research Grants R01 HL073952 and HL071933 (to S.N.G.), COPD SCCOR P50 HL084945 and CA 94076 (to T.W.K.) and by NIH NIEHS Pilot Project Grants P30 ES03819 and P30 ES001247 (to M.A.W.).
M.A.W. wrote the paper, performed the research, analyzed the data, and was responsible for the design and implementation of the experiments. T.R. cowrote the paper, performed the research with M.A.W., and assisted with the analysis of the data as well as with the design and implementation of the experiments. S.K. assisted with the technical aspects of the experiments and also contributed important elements for the design and implementation of some of the experiments. M.K. provided important technical assistance and data analysis in the execution of some of the experimental assays. S.M.B. assisted with the design and implementation of the data derived from lung DCs and naive CD4+ T cell coculture studies as well as with the measurement of cytokine production. T.W.K. provided vital new reagents and analytical tools and assisted with analysis of some of the data. M.Y. contributed vital materials to this study. P.B. contributed vital materials to this study as well as methodological approaches in using particulate matter. S.B. assisted in the experimental design and data analysis. S.N.G. assisted in the experimental design, critical discussion, and data analysis.
2 M.A.W. and T.R. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Marc. A. Williams or Dr. Steve N. Georas, Division of Pulmonary and Critical Care Medicine, University of Rochester School of Medicine, 601 Elmwood Avenue, Box 692, Rochester, NY 14642-8692. E-mail addresses: marc_williams{at}urmc.rochester.edu or steve_georas{at}urmc.rochester.edu
4 Abbreviations used in this paper: PM, particulate matter; APM, ambient particulate matter; CD40L, CD40 ligand; DC, dendritic cell; DCF, dichlorofluorescein; DCFH-DA, 2',7'-dichlorofluorescein diacetate; DX, dextran; GCLc, glutathione cysteine ligase catalytic subunit; GCLm, GCLc modifier subunit; HO-1, hemeoxygenase-1; KC, keratinocyte; MFI, mean fluorescence intensity; NAC, N-acetyl cysteine; Nrf2, nuclear erythroid 2 p45-related factor 2; PDCA-1, plasmacytoid DC Ag-1; ROS, reactive oxygen species; VEGF, vascular endothelial growth factor; wt, wild type.
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