Article

Nuclear erythroid 2 p45-related factor 2 inhibits the maturation of murine dendritic cells by ragweed extract.

Department of Environmental Health Sciences, Johns Hopkins University, Baltimore, MD 21205, USA.
American Journal of Respiratory Cell and Molecular Biology (Impact Factor: 4.11). 10/2009; 43(3):276-85. DOI: 10.1165/rcmb.2008-0438OC
Source: PubMed

ABSTRACT Oxidative stress plays an important role in immune regulation and dendritic cell (DC) maturation. Recent studies indicate that allergens, including ragweed extract (RWE), possess prooxidant activities, but how RWE interacts with DCs is not well understood. Nuclear erythroid 2 p45-related factor 2 (Nrf2) is a key transcription factor that regulates constitutive and coordinated induction of a battery of antioxidant genes. We hypothesized that RWE would activate DCs and that this response would be augmented in the absence of Nrf2. We generated bone marrow-derived DCs (BM-DCs) and isolated lung DCs from Nrf2(+/+) and Nrf2(-/-) mice and studied the effects of RWE on DCs in vitro. Under resting conditions, Nrf2(-/-) BM-DCs exhibited constitutively greater levels of inflammatory cytokines and costimulatory molecules than Nrf2(+/+) BM-DCs. Exposure to RWE impaired endocytic activity, significantly induced oxidative stress, and enhanced the expression of CD80, CD86, and MHCII in Nrf2(-/-) BM-DCs when compared with Nrf2(+/+) BM-DC, in association with reduced expression of Nrf2-regulated antioxidant genes. RWE significantly induced the secretion of inflammatory cytokines IL-6 and TNF-alpha in BM-DCs and lung DCs from Nrf2(-/-) mice than Nrf2(+/+) mice and significantly inhibited the secretion of IL-12 in Nrf2(+/+) BM-DCs and IL-18 in Nrf2(+/+) and Nrf2(-/-) BM-DCs. The stimulatory effects of RWE on DC activation were inhibited to varying degrees by the antioxidant N-acetyl cysteine. Our findings indicate that a defect in Nrf2-mediated signaling mechanisms alters the response of DCs to a common environmental allergen, which may contribute to the susceptibility to allergic diseases.

0 Followers
 · 
154 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The past 15 years have seen enormous advances in our understanding of the receptor and signalling systems that allow dendritic cells (DCs) to respond to pathogens or other danger signals and initiate innate and adaptive immune responses. We are now beginning to appreciate that many of these pathways not only stimulate changes in the expression of genes that control DC immune functions, but also affect metabolic pathways, thereby integrating the cellular requirements of the activation process. In this Review, we focus on this relatively new area of research and attempt to describe an integrated view of DC immunometabolism.
    Nature reviews. Immunology 12/2014; 15(1):18-29. DOI:10.1038/nri3771 · 33.84 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: L’asthme est une maladie chronique des voies aériennes qui s’accompagne de modifications importantes des cellules de structure du poumon. Ainsi, on observe, chez les patients atteints d’asthme, des altérations de l’intégrité de la barrière épithéliale ainsi que l’augmentation du nombre de cellules productrices de mucus au sein de l’épithélium. Pendant très longtemps, ces changements ont été considérés comme le résultat final de la réaction inflammatoire pulmonaire, une sorte de cicatrisation en réponse à une inflammation chronique. Cependant, ces dernières années, il a été montré que les cellules de structure pulmonaires joueraient un rôle prédominant dans la cascade allergique. Cette revue discutera du rôle de l’épithélium pulmonaire, considéré comme un régulateur crucial de la réponse immunitaire inflammatoire développée contre les allergènes, les virus et les polluants.
    Revue Française d Allergologie 10/2012; 52(6):457-461. DOI:10.1016/j.reval.2012.05.006 · 0.22 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The aim of the present review was to discuss the effects of pollen components on innate immune responses. Pollens contain numerous factors that can stimulate an innate immune response. These include intrinsic factors in pollens such as nicotinamide adenine dinucleotide phosphate oxidases, proteases, aqueous pollen proteins, lipids, and antigens. Each component stimulates innate immune response in a different manner. Pollen nicotinamide adenine dinucleotide phosphate oxidases induce reactive oxygen species generation and recruit neutrophils that stimulate subsequent allergic inflammation. Pollen proteases damage epithelial barrier function and increase antigen uptake. Aqueous pollen extract proteins and pollen lipids modulate dendritic cell function and induce Th2 polarization. Clinical studies have shown that modulation of innate immune response to pollens with toll-like receptor 9- and toll-like receptor 4-stimulating conjugates is well tolerated and induces clear immunological effects, but is not very effective in suppressing primary clinical endpoints of allergic inflammation. Additional research on innate immune pathways induced by pollen components is required to develop novel strategies that will mitigate the development of allergic inflammation.
    Current Opinion in Allergy and Clinical Immunology 02/2015; 15(1):79-88. DOI:10.1097/ACI.0000000000000136 · 3.66 Impact Factor