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: 3.99). 10/2009; 43(3):276-85. DOI: 10.1165/rcmb.2008-0438OC
Source: PubMed


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.

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    • "Moreover, resveratrol, a drug that has been linked to induction of tolerogenic DCs, is thought to favor catabolic metabolism through activation of the histone deacetylase Sirtuin 1, which is known to suppress HIF-1α function as well as enhance PGC-1α activity (29, 32, 53). In addition, DCs deficient for Nuclear factor-erythroid 2 p45-related factor-2 (NRF2) or PPAR-γ, downstream targets of PGC-1α, display increased maturation and T cell priming capacity (31, 54, 55). Hence, these studies may point toward an important role for the AMPK-PGC-1α axis in promoting mitochondria-centered catabolic metabolism in DCs, which may be crucial for the acquisition of a tolerogenic phenotype (Figure 2). "
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    ABSTRACT: Dendritic cells (DCs) are key regulators of both immunity and tolerance by controlling activation and polarization of effector T helper cell and regulatory T cell responses. Therefore, there is a major focus on developing approaches to manipulate DC function for immunotherapy. It is well known that changes in cellular activation are coupled to profound changes in cellular metabolism. Over the past decade there is a growing appreciation that these metabolic changes also underlie the capacity of immune cells to perform particular functions. This has led to the concept that the manipulation of cellular metabolism can be used to shape innate and adaptive immune responses. While most of our understanding in this area has been gained from studies with T cells and macrophages, evidence is emerging that the activation and function of DCs are also dictated by the type of metabolism these cells commit to. We here discuss these new insights and explore whether targeting of metabolic pathways in DCs could hold promise as a novel approach to manipulate the functional properties of DCs for clinical purposes.
    Frontiers in Immunology 05/2014; 5:203. DOI:10.3389/fimmu.2014.00203
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    • "However, oxidative stress also activates nuclear erythroid 2 p45-related factor 2 (Nrf2), a transcription factor that positively regulates many antioxidant genes [50]. A recent study demonstrated that DCs isolated from Nrf2-deficient mice secreted significantly higher amounts of IL-6 and TNF-α after exposure to ragweed pollen extract than DCs from wild-type mice [50]. Furthermore, we recently reported that ragweed pollen grain treatment increased the production of IL-8, TNF-α, and IL-6 by human moDCs, and this effect was decreased by antioxidants [24]. "
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    ABSTRACT: Ragweed (Ambrosia artemisiifolia) pollen grains, which are generally considered too large to reach the lower respiratory tract, release subpollen particles (SPPs) of respirable size upon hydration. These SPPs contain allergenic proteins and functional NAD(P)H oxidases. In this study, we examined whether exposure to SPPs initiates the activation of human monocyte-derived dendritic cells (moDCs). We found that treatment with freshly isolated ragweed SPPs increased the intracellular levels of reactive oxygen species (ROS) in moDCs. Phagocytosis of SPPs by moDCs, as demonstrated by confocal laser-scanning microscopy, led to an up-regulation of the cell surface expression of CD40, CD80, CD86, and HLA-DQ and an increase in the production of IL-6, TNF-α, IL-8, and IL-10. Furthermore, SPP-treated moDCs had an increased capacity to stimulate the proliferation of naïve T cells. Co-culture of SPP-treated moDCs with allogeneic CD3(+) pan-T cells resulted in increased secretion of IFN-γ and IL-17 by T cells of both allergic and non-allergic subjects, but induced the production of IL-4 exclusively from the T cells of allergic individuals. Addition of exogenous NADPH further increased, while heat-inactivation or pre-treatment with diphenyleneiodonium (DPI), an inhibitor of NADPH oxidases, strongly diminished, the ability of SPPs to induce phenotypic and functional changes in moDCs, indicating that these processes were mediated, at least partly, by the intrinsic NAD(P)H oxidase activity of SPPs. Collectively, our data suggest that inhaled ragweed SPPs are fully capable of activating dendritic cells (DCs) in the airways and SPPs' NAD(P)H oxidase activity is involved in initiation of adaptive immune responses against innocuous pollen proteins.
    PLoS ONE 12/2012; 7(12):e52085. DOI:10.1371/journal.pone.0052085 · 3.23 Impact Factor
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    ABSTRACT: Immune responses can be compartmentalized into innate versus adaptive components. This relatively recent dichotomy positioned the innate immune system at the interface between the host and the external environment and provided a new conceptual framework with which to view allergic diseases, including asthma. Airway epithelial cells and dendritic cells are key components of the innate immune system in the nose and lung and are now known to be intimately involved in allergen recognition and in modulating allergic immune responses. Here we review current thinking about how these two key cell types sense and respond to inhaled allergens, and emphasize how an understanding of "allergic innate immunity" can translate into new thinking about mechanisms of allergen sensitization and potentially lead to new therapeutic targets.
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