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Spatial Interactions between Dendritic Cells and Sensory Nerves in Allergic Airway Inflammation

¹ Department of Immunology, Allergology and Immunotoxicology, Fraunhofer Institute of Toxicology and Experimental Medicine, Hannover, Germany; ² Clinical Research Unit of Allergy, Charité Campus-Virchow, Charité School of Medicine, Humboldt University, Berlin, Germany; ³ Cytological Laboratory, Hospital Grosshansdorf, Centre for Pneumology and Thoracic Surgery, Grosshansdorf, Germany; and ⁴ Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russia

Correspondence and requests for reprints should be addressed to Armin Braun, Ph.D., Dept. of Immunology, Allergology and Immunotoxicology, Fraunhofer Institute of Toxicology and Experimental Medicine, 30625 Hannover, Germany. E-mail: braun{at}item.fraunhofer.de

Neuroimmune interactions play a critical role in the pathogenesis of asthma. Symptoms like wheezing and cough have been attributed to neural dysregulation, whereas sensitization and the induction of allergic inflammation have been linked with the activity of dendritic cells. Neuropeptides were previously shown to control dendritic cell function in vitro, suggesting interactions between dendritic cells and sensory nerves. Here we characterized the anatomical basis of the interactions between dendritic cells and nerves in the airways of mice and monitored the changes during allergic inflammation. Airway microdissection, whole-mount immunohistology, and confocal microscopy were used for the three-dimensional quantitative mapping of airway nerves and dendritic cells along the main axial pathway of nonsensitized versus ovalbumin-sensitized and -challenged CD11c-enhanced yellow fluorescent protein (CD11c-EYFP) transgenic mice. CD11c-EYFP–positive airway mucosal dendritic cells were contacted by calcitonin gene-related peptide–immunoreactive sensory fibers and their co-localization increased in allergic inflammation. Moreover, protein gene product 9.5–positive neuroepithelial bodies and airway ganglia were associated with dendritic cells. In human airways, human leukocyte antigen DR–positive mucosal dendritic cells were found in the close proximity of sensory nerves and neuroepithelial cells. These results provide morphologic evidence of the interactions between dendritic cells and the neural network of the airways at multiple anatomical sites.

Key Words: airway nerves • dendritic cells • neuroimmune interactions • asthma

CLINICAL RELEVANCE Here we identify anatomical sites at which airway dendritic cells are contacted by various neural structures in health and in allergic inflammation, providing a link between the neural dysregulation and the immunological changes associated with asthma.