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Aeroallergen provocation induces the rapid accumulation of CDllc+MHC class II (MHC II)+ dendritic cells (DCs) in the lungs, which is driven by an increased recruitment of blood-derived DC precursors. Recent data show, however, that well-differentiated DCs proliferate in situ in various tissues. This may also contribute to their allergen-induced expansion; therefore, we studied DC proliferation in the airways of mice in the steady state and after local aeroallergen provocation. Confocal whole-mount microscopy was used to visualize proliferating DCs in different microanatomical compartments of the lung. We demonstrate that in the steady state, CDllc+MHC II+ DCs proliferate in both the epithelial and subepithelial layers of the airway mucosa as well as in the lung parenchyma. A 1-h pulse of the nucleotide 5-ethynyl-2'-deoxyuridine was sufficient to label 5% of DCs in both layers of the airway mucosa. On the level of whole-lung tissue, 3-5% of both CDllb+ and CDllb- DC populations and 0.3% of CDllc+MHC IIlow lung macrophages incorporated 5-ethynyI-2'-deoxyuridine. Aeroallergen provocation caused a 3-fold increase in the frequency of locally proliferating DCs in the airway mucosa. This increase in mucosal DC proliferation was later followed by an elevation in the number of DCs. The recruitment of monocyte-derived inflammatory DCs contributed to the increasing number of DCs in the lung parenchyma, but not in the airway mucosa. We conclude that local proliferation significantly contributes to airway DC homeostasis in the steady state and that it is the major mechanism underlying the expansion of the mucosal epithelial/subepithelial DC network in allergic inflammation. [ABSTRACT FROM AUTHOR]

The airway mucosal epithelium is permanently exposed to airborne particles. A network of immune cells patrols at this interface to the environment. The interplay of immune cells is orchestrated by different mediators. In the current study we investigated the impact of neuronal signals on key functions of dendritic cells (DC). Using two-photon microscopic time-lapse analysis of living lung sections from CD11c-EYFP transgenic mice we studied the influence of neuropeptides on airway DC motility. Additionally, using a confocal microscopic approach, the phagocytotic capacity of CD11c+ cells after neuropeptide stimulation was determined. Electrical field stimulation (EFS) leads to an unspecific release of neuropeptides from nerves. After EFS and treatment with the neuropeptides vasoactive intestinal peptide (VIP) or calcitonin gene-related peptide (CGRP), airway DC in living lung slices showed an altered motility. Furthermore, the EFS-mediated effect could partially be blocked by pre-treatment with the receptor antagonist CGRP8-37. Additionally, the phagocytotic capacity of bone marrow-derived and whole lung CD11c+ cells could be inhibited by neuropeptides CGRP, VIP, and Substance P. We then cross-linked these data with the in vivo situation by analyzing DC motility in two different OVA asthma models. Both in the acute and prolonged OVA asthma model altered neuropeptide amounts and DC motility in the airways could be measured. In summary, our data suggest that neuropeptides modulate key features motility and phagocytosis of mouse airway DC. Therefore altered neuropeptide levels in airways during allergic inflammation have impact on regulation of airway immune mechanisms and therefore might contribute to the pathophysiology of asthma. [ABSTRACT FROM AUTHOR]