Attenuated allergic airway inflammation in Cd39 null mice (original) (raw)
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Extracellular ATP triggers and maintains asthmatic airway inflammation by activating dendritic cells
Nature Medicine, 2007
Extracellular ATP serves as a danger signal to alert the immune system of tissue damage by acting on P2X or P2Y receptors. Here we show that allergen challenge causes acute accumulation of ATP in the airways of asthmatic subjects and mice with experimentally induced asthma. All the cardinal features of asthma, including eosinophilic airway inflammation, Th2 cytokine production and bronchial hyper-reactivity, were abrogated when lung ATP levels were locally neutralized using apyrase or when mice were treated with broad-spectrum P2-receptor antagonists. In addition to these effects of ATP in established inflammation, Th2 sensitization to inhaled antigen was enhanced by endogenous or exogenous ATP. The adjuvant effects of ATP were due to the recruitment and activation of lung myeloid dendritic cells that induced Th2 responses in the mediastinal nodes. Together these data show that purinergic signaling has a key role in allergen-driven lung inflammation that is likely to be amenable to therapeutic intervention.
Journal of Immunology, 2011
The molecular mechanisms underlying the initiation of innate and adaptive proallergic Th2-type responses in the airways are not well understood. IL-33 is a new member of the IL-1 family of molecules that is implicated in Th2-type responses. Airway exposure of naive mice to a common environmental aeroallergen, the fungus Alternaria alternata, induces rapid release of IL-33 into the airway lumen, followed by innate Th2-type responses. Biologically active IL-33 is constitutively stored in the nuclei of human airway epithelial cells. Exposing these epithelial cells to A. alternata releases IL-33 extracellularly in vitro. Allergen exposure also induces acute extracellular accumulation of a danger signal, ATP; autocrine ATP sustains increases in intracellular Ca 2+ concentration and releases IL-33 through activation of P2 purinergic receptors. Pharmacological inhibitors of purinergic receptors or deficiency in the P2Y2 gene abrogate IL-33 release and Th2-type responses in the Alternaria-induced airway inflammation model in naive mice, emphasizing the essential roles for ATP and the P2Y 2 receptor. Thus, ATP and purinergic signaling in the respiratory epithelium are critical sensors for airway exposure to airborne allergens, and they may provide novel opportunities to dampen the hypersensitivity response in Th2-type airway diseases such as asthma.
Immunity, 2013
Dendritic cells (DCs) are crucial for mounting allergic airway inflammation, but it is unclear which subset of DCs performs this task. By using CD64 and MAR-1 staining, we reliably separated CD11b + monocytederived DCs (moDCs) from conventional DCs (cDCs) and studied antigen uptake, migration, and presentation assays of lung and lymph node (LN) DCs in response to inhaled house dust mite (HDM). Mainly CD11b + cDCs but not CD103 + cDCs induced T helper 2 (Th2) cell immunity in HDM-specific T cells in vitro and asthma in vivo. Studies in Flt3l À/À mice, lacking all cDCs, revealed that moDCs were also sufficient to induce Th2 cell-mediated immunity but only when high-dose HDM was given. The main function of moDCs was the production of proinflammatory chemokines and allergen presentation in the lung during challenge. Thus, we have identified migratory CD11b + cDCs as the principal subset inducing Th2 cell-mediated immunity in the LN, whereas moDCs orchestrate allergic inflammation in the lung. Immunity moDCs and cDCs in Asthma Immunity 38, 322-335, February 21, 2013 ª2013 Elsevier Inc. 323
Allergy, asthma & immunology research, 2018
The use of tolerogenic dendritic cells (TolDCs) to control exacerbated immune responses may be a prophylactic and therapeutic option for application in autoimmune and allergic conditions. The objective of this work was to evaluate the effects of TolDC administration in a mouse model of allergic airway inflammation caused by mite extract. Mouse bone marrow-derived TolDCs were induced by incubation with granulocyte-macrophage colony-stimulating factor (GM-CSF) and dexamethasone, and then characterized by flow cytometry and cytokine production by enzyme-linked immunosorbent assay (ELISA). For the in vivo model of Blomia tropicalis-induced allergy, mice transplanted with antigen-pulsed TolDCs were sensitized intraperitoneally with B. tropicalis mite extract (BtE) adsorbed to aluminium hydroxide. After challenge by nasal administration of BtE, bronchoalveolar lavage fluid (BALF), lungs, spleen and serum were collected for analysis. Induction of TolDCs was efficiently achieved as shown by...
CD38 Plays a Dual Role in Allergen-Induced Airway Hyperresponsiveness
American Journal of Respiratory Cell and Molecular Biology, 2008
The multifunctional surface protein CD38 acts as a receptor with ecto-enzymatic activity, hydrolyzing NAD to generate several products known to exhibit Ca 21 -mobilizing properties. Although CD38 is a convenient marker of immune cell development, and an indicator of progression for several diseases, it is not restricted to the immune compartment. To determine the potentially multilayered involvement of CD38 in allergen-induced airway inflammation and hyperreactivity, we dissected the potential role of CD38 as a regulator of immunity, but also pulmonary function. CD38-deficient and wildtype (WT) mice were sensitized and airway challenged with ovalbumin, and subsequently analyzed regarding their level of airway hyperresponsiveness (AHR) in response to methacholine. Parameters of lung inflammation were also analyzed. Similar sets of measurements were obtained from reciprocal bone marrow swapping experiments between CD38 2/2 and WT mice. Mice lacking CD38 exhibit strongly reduced AHR, which is accompanied by a decrease in typical hallmarks of pulmonary inflammation, including eosinophilia and lymphocytic lung infiltrates, as well as Th2-cytokine levels (IL-4, -5, and -13). Antigen-specific immunoglobulin (Ig)E and IgG1 antibody titers are substantially reduced, consistent with CD38 being crucial for mounting a primary humoral systemic immune response. Reconstitution of lethally irradiated, lung-shielded, CD38deficient mice with WT bone marrow does not restore WT levels of airway hyperreactivity, nor mucus secretion. The opposite experiment, transferring CD38 2/2 bone marrow into WT mice, also shows reduced AHR levels. These studies demonstrate that CD38 not only acts as a key modulator of the immune response, but also plays an equally important role as an intrinsic pulmonary component.
The Journal of allergy and clinical immunology, 2017
Exposure to allergens like house dust mite (HDM) via the skin often precedes allergic inflammation in the lung. It was proposed that Th2 sensitization via the skin occurs when skin barrier function is disrupted for example by genetic predisposition, mechanical damage or enzymatic activity of allergens. To study how HDM applied to unmanipulated skin leads to Th2 sensitization and to study which antigen presenting cells mediate this process METHODS: HDM was applied epicutaneously by painting HDM on unmanipulated ear skin, or under an occlusive tape. HDM challenge was via the nose. Mouse strains lacking different dendritic cell (DC) populations were used, and 1-DER T cells carrying a transgenic TCR reactive to Der p 1 allergen used as readout for antigen presentation. The Th2-inducing capacity of sorted skin-derived DC subsets was determined by adoptive transfer to naïve mice. Epicutaneous HDM application led to Th2 sensitization and eosinophilic airway inflammation upon intranasal HDM...
House dust mite induced allergic airway disease is attenuated in CD11ccreIL-4Rα−/l°x mice
Scientific Reports, 2018
The precise mechanisms leading to development of T helper type (Th)2-driven allergic responses are unknown. We aimed to determine how IL-4 receptor alpha (IL-4Rα) signaling on CD11c + cells influences allergen-induced Th2 responses in mice. CD11c cre IL-4Rα −/l°x mice, deficient in IL-4Rα on dendritic cells and alveolar macrophages, were compared to IL-4Rα −/l°x littermate controls in models of allergic airway disease induced by OVA/alum, OVA alone or house dust mite. Cytokine responses, eosinophil and neutrophil infiltration into the lungs, airway hyperreactivity and mucus hypersecretion were evaluated after allergen challenge. In the OVA/alum model, CD11c cre IL-4Rα −/lox mice had similar airway hyperreactivity, eosinophil infiltration, Th2-type cytokine production and mucus hypersecretion to littermate controls. When alum was omitted during sensitization, CD11c cre IL-4Rα −/lox mice had similar airway hyperreactivity and mucus secretion but reduced Th2-type cytokine production and eosinophils, suggesting alum overrides the requirement for IL-4Rα signaling on CD11c + cells in enhancing Th2-type responses. In the house dust mite model, CD11c cre IL-4Rα −/lox mice showed similar mucus secretion, but reduced Th2 responses, eosinophils, neutrophils and airway hyperreactivity, unlike previously tested LysM cre IL-4Rα −/lox mice, which lack IL-4Rα on alveolar macrophages but not on dendritic cells. Therefore, our results indicate that IL-4Rα signaling on dendritic cells promotes allergen-induced Th2 responses and eosinophil infiltration into the lung.
Journal of immunology (Baltimore, Md. : 1950), 2011
Chronic innocuous aeroallergen exposure attenuates CD4(+) T cell-mediated airways hyperresponsiveness in mice; however, the mechanism(s) remain unclear. We examined the role of airway mucosal dendritic cell (AMDC) subsets in this process using a multi-OVA aerosol-induced tolerance model in sensitized BALB/c mice. Aeroallergen capture by both CD11b(lo) and CD11b(hi) AMDC and the delivery of OVA to airway draining lymph nodes by CD8α(-) migratory dendritic cells (DC) were decreased in vivo (but not in vitro) when compared with sensitized but nontolerant mice. This was functionally significant, because in vivo proliferation of OVA-specific CD4(+) T cells was suppressed in airway draining lymph nodes of tolerized mice and could be restored by intranasal transfer of OVA-pulsed and activated exogenous DC, indicating a deficiency in Ag presentation by endogenous DC arriving from the airway mucosa. Bone marrow-derived DC Ag-presenting function was suppressed in multi-OVA tolerized mice, and...