Reducing Lung ATP Levels and Alleviating Asthmatic Airway Inflammation through Adeno-Associated Viral Vector-Mediated CD39 Expression.
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ABSTRACT:
SUBMITTER: Huang YA
PROVIDER: S-EPMC8228057 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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.
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Project description:Inflammation, airway hyper-responsiveness and airway remodelling are well-established hallmarks of asthma, but their inter-relationships remain elusive. In order to obtain a better understanding of their inter-dependence, we develop a mechanochemical morphoelastic model of the airway wall accounting for local volume changes in airway smooth muscle (ASM) and extracellular matrix in response to transient inflammatory or contractile agonist challenges. We use constrained mixture theory, together with a multiplicative decomposition of growth from the elastic deformation, to model the airway wall as a nonlinear fibre-reinforced elastic cylinder. Local contractile agonist drives ASM cell contraction, generating mechanical stresses in the tissue that drive further release of mitogenic mediators and contractile agonists via underlying mechanotransductive signalling pathways. Our model predictions are consistent with previously described inflammation-induced remodelling within an axisymmetric airway geometry. Additionally, our simulations reveal novel mechanotransductive feedback by which hyper-responsive airways exhibit increased remodelling, for example, via stress-induced release of pro-mitogenic and pro-contractile cytokines. Simulation results also reveal emergence of a persistent contractile tone observed in asthmatics, via either a pathological mechanotransductive feedback loop, a failure to clear agonists from the tissue, or a combination of both. Furthermore, we identify various parameter combinations that may contribute to the existence of different asthma phenotypes, and we illustrate a combination of factors which may predispose severe asthmatics to fatal bronchospasms.
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