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Attenuated allergic airway inflammation in Cd39 null mice.

ABSTRACT: Extracellular Adenosine-5'-Triphosphate (ATP) is known to accumulate in the lung, following allergen challenge, and contributes via activation of purinergic receptors on dendritic cells (DC), to the development of allergic airway inflammation (AAI). Extracellular ATP levels in the airways are normally tightly regulated by CD39. This ectonucleotidase is highly expressed by DC purified from skin (Langerhans cells) and bone marrow, and has been shown to modulate DC adaptive/haptenic immune responses. In this study, we have evaluated the impact of Cd39 deletion and associated perturbation of purinergic signaling in AAI.Standard ovalbumin (OVA)-alum and house dust mite (HDM) bone marrow-derived DC (BMDC)-dependent models of AAI were used to study effects of Cd39. Migration assays, time lapse microscopy, and T-cell priming assays were further used to determine functional relevance of Cd39 expression on BMDC in the setting of immune and Th2-mediated responses in these models.Cd39(-/-) mice exhibited marked increases in BALF ATP levels but paradoxically exhibited limited AAI in both OVA-alum and HDM models. These pathophysiological abnormalities were associated with decreased myeloid DC activation and chemotaxis toward ATP, and were linked to purinergic receptor desensitization responses. Further, Cd39(-/-) DCs exhibited limited capacity to both prime Th2 responses and form stable immune synaptic interactions with OVA-transgenic naïve T cells.Cd39-deficient DCs exhibit limited capacity to induce Th2 immunity in a DC-driven model of AAI in vivo. Our data demonstrate a role of CD39 and perturbed purinergic signaling in models of AAI.

SUBMITTER: Idzko M

PROVIDER: S-EPMC5291121 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Attenuated allergic airway inflammation in Cd39 null mice.

Idzko M M K Ayata C C Müller T T Dürk T T Grimm M M Baudiß K K Vieira R P RP Cicko S S Boehlke C C Zech A A Sorichter S S Pelletier J J Sévigny J J Robson S C SC

Allergy 20130301 4

<h4>Background</h4>Extracellular Adenosine-5'-Triphosphate (ATP) is known to accumulate in the lung, following allergen challenge, and contributes via activation of purinergic receptors on dendritic cells (DC), to the development of allergic airway inflammation (AAI). Extracellular ATP levels in the airways are normally tightly regulated by CD39. This ectonucleotidase is highly expressed by DC purified from skin (Langerhans cells) and bone marrow, and has been shown to modulate DC adaptive/hapte ...[more]

PMID: 23452076

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Project description:BACKGROUND:Serum IL-22 levels are increased in patients with atopic dermatitis, which commonly precedes asthma in the atopic march. Epicutaneous sensitization in mice results in TH2-dominated skin inflammation that mimics atopic dermatitis and sensitizes the airways for antigen challenge-induced allergic inflammation characterized by the presence of both eosinophils and neutrophils. Epicutaneous sensitization results in increased serum levels of IL-22. OBJECTIVE:We sought to determine the role of IL-22 in antigen-driven airway allergic inflammation after inhalation challenge in epicutaneously sensitized mice. METHODS:Wild-type (WT) and Il22-/- mice were sensitized epicutaneously or immunized intraperitoneally with ovalbumin (OVA) and challenged intranasally with antigen. OVA T-cell receptor-specific T cells were TH22 polarized in vitro. Airway inflammation, mRNA levels in the lungs, and airway hyperresponsiveness (AHR) were examined. RESULTS:Epicutaneous sensitization preferentially elicited an IL-22 response compared with intraperitoneal immunization. Intranasal challenge of mice epicutaneously sensitized with OVA elicited in the lungs Il22 mRNA expression, IL-22 production, and accumulation of CD3+CD4+IL-22+ T cells that coexpressed IL-17A and TNF-?. Epicutaneously sensitized Il22-/- mice exhibited diminished eosinophil and neutrophil airway infiltration and decreased AHR after intranasal OVA challenge. Production of IL-13, IL-17A, and TNF-? was normal, but IFN-? production was increased in lung cells from airway-challenged and epicutaneously sensitized Il22-/- mice. Intranasal instillation of IFN-?-neutralizing antibody partially reversed the defect in eosinophil recruitment. WT recipients of TH22-polarized WT, but not IL-22-deficient, T-cell receptor OVA-specific T cells, which secrete both IL-17A and TNF-?, had neutrophil-dominated airway inflammation and AHR on intranasal OVA challenge. Intranasal instillation of IL-22 with TNF-?, but not IL-17A, elicited neutrophil-dominated airway inflammation and AHR in WT mice, suggesting that loss of IL-22 synergy with TNF-? contributed to defective recruitment of neutrophils into the airways of Il22-/- mice. TNF-?, but not IL-22, blockade at the time of antigen inhalation challenge inhibited airway inflammation in epicutaneously sensitized mice. CONCLUSION:Epicutaneous sensitization promotes generation of antigen-specific IL-22-producing T cells that promote airway inflammation and AHR after antigen challenge, suggesting that IL-22 plays an important role in the atopic march.

Project description:BackgroundAs one of the main functional forms of mesenchymal stem cells (MSCs), MSC-derived extracellular vesicles (MSC-EVs) have shown an alternative therapeutic option in experimental models of allergic asthma. Oxygen concentration plays an important role in the self-renewal, proliferation, and EV release of MSCs and a recent study found that the anti-asthma effect of MSCs was enhanced by culture in hypoxic conditions. However, the potential of hypoxic MSC-derived EVs (Hypo-EVs) in asthma is still unknown.MethodsBALB/c female mice were sensitized and challenged with ovalbumin (OVA), and each group received PBS, normoxic human umbilical cord MSC-EVs (Nor-EVs), or Hypo-EVs weekly. After treatment, the animals were euthanized, and their lungs and bronchoalveolar lavage fluid (BALF) were collected. With the use of hematoxylin and eosin (HE), periodic acid-Schiff (PAS) and Masson's trichrome staining, enzyme-linked immune sorbent assay (ELISA), Western blot analysis, and real-time PCR, the inflammation and collagen fiber content of airways and lung parenchyma were investigated.ResultsHypoxic environment can promote human umbilical cord MSCs (hUCMSCs) to release more EVs. In OVA animals, the administration of Nor-EVs or Hypo-EVs significantly ameliorated the BALF total cells, eosinophils, and pro-inflammatory mediators (IL-4 and IL-13) in asthmatic mice. Moreover, Hypo-EVs were generally more potent than Nor-EVs in suppressing airway inflammation in asthmatic mice. Compared with Nor-EVs, Hypo-EVs further prevented mouse chronic allergic airway remodeling, concomitant with the decreased expression of pro-fibrogenic markers α-smooth muscle actin (α-SMA), collagen-1, and TGF-β1-p-smad2/3 signaling pathway. In vitro, Hypo-EVs decreased the expression of p-smad2/3, α-SMA, and collagen-1 in HLF-1 cells (human lung fibroblasts) stimulated by TGF-β1. In addition, we showed that miR-146a-5p was enriched in Hypo-EVs compared with that in Nor-EVs, and Hypo-EV administration unregulated the miR-146a-5p expression both in asthma mice lung tissues and in TGF-β1-treated HLF-1. More importantly, decreased miR-146a-5p expression in Hypo-EVs impaired Hypo-EV-mediated lung protection in OVA mice.ConclusionOur findings provided the first evidence that hypoxic hUCMSC-derived EVs attenuated allergic airway inflammation and airway remodeling in chronic asthma mice, potentially creating new avenues for the treatment of asthma.

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Attenuated allergic airway inflammation in Cd39 null mice.

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Attenuated allergic airway inflammation in Cd39 null mice.

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