Neuropeptides control the dynamic behavior of airway mucosal dendritic cells.

Sabrina Voedisch,Sabine Rochlitzer,Armin Braun,Tibor Z Veres,Emma Spies,Christian Taube

doi:10.1371/journal.pone.0045951

Abstract

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.

Highlights

The airways are permanently exposed to environmental stimuli such as temperature and humidity shifts, airborne pathogens, pollen and smoke particles, or ozone
In order to characterize these cells in mouse main bronchi, airway whole-mounts of CD11cEYFP transgenic mice [19] were stained with a combination of markers discriminating between dendritic cells (DC) and other cell types like e.g. macrophages such as CD11c, major histocompatibility complex class II (MHC-II), CD68, and F4/80
Because it appears that in both transgenic mice the same cell population is illuminated by their reporter fluorescence in the airway mucosa, we concluded that most CD11c+ cells in mouse main bronchus epithelium show markers described to be characteristic for lung DC

Summary

Introduction

The airways are permanently exposed to environmental stimuli such as temperature and humidity shifts, airborne pathogens, pollen and smoke particles, or ozone. To enable homeostasis of lung physiology several mechanisms exist to compensate this blast of influences. Down the cascade of defense mechanisms (mucociliary elevator, IgA, epithelial barrier), a multitude of immune cells patrols below the epithelial layer to intercept foreign particles and antigens. Macrophages and dendritic cells (DC) capture, process and present incoming antigen and initiate appropriate immune responses. Nerves co-localizing with DC below the epithelial layer respond to chemical, mechanical or inflammatory stimuli and on their part interact with the surrounding cells via neurotransmitters and neuropeptides. DC and other immune cells can receive these neurogenic signals by expressing neuropeptide receptors [1,2,3,4]

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Results

Conclusion