title: The neuropeptide calcitonin gene-related peptide affects allergic airway inflammation by modulating dendritic cell function.
abstract: BACKGROUND
  The neuropeptide calcitonin gene-related peptide (CGRP) is released in the lung by sensory nerves during allergic airway responses. Pulmonary dendritic cells (DC) orchestrating the allergic inflammation could be affected by CGRP.
  
  
  OBJECTIVE
  To determine the immunomodulatory effects of CGRP on DC function and its impact on the induction of allergic airway inflammation.
  
  
  METHODS
  CGRP receptor expression on lung DC was determined by RT-PCR and immunofluorescence staining. The functional consequences of CGRP receptor triggering were evaluated in vitro using bone marrow-derived DC. DC maturation and the induction of ovalbumin (OVA)-specific T cell responses were analysed by flow cytometry. The in vivo relevance of the observed DC modulation was assessed in a DC-transfer model of experimental asthma. Mice were sensitized by an intrapharyngeal transfer of OVA-pulsed DC and challenged with OVA aerosol. The impact of CGRP pretreatment of DC on airway inflammation was characterized by analysing differential cell counts and cytokines in bronchoalveolar lavage fluid (BALF), lung histology and cytokine responses in mediastinal lymph nodes.
  
  
  RESULTS
  RT-PCR, immunofluorescence and cAMP assay demonstrated the expression of functionally active CGRP receptors in lung DC. RT-PCR revealed a transcriptional CGRP receptor down-regulation during airway inflammation. CGRP specifically inhibited the maturation of in vitro generated DC. Maturation was restored by blocking with the specific antagonist CGRP(8-37) . Consequently, CGRP-pretreated DC reduced the activation and proliferation of antigen-specific T cells and induced increased the numbers of T regulatory cells. The transfer of CGRP-pretreated DC diminished allergic airway inflammation in vivo, shown by reduced eosinophil numbers and increased levels of IL-10 in BALF.
  
  
  CONCLUSIONS
  CGRP inhibits DC maturation and allergen-specific T cell responses, which affects the outcome of the allergic airway inflammation in vivo. This suggests an additional mechanism by which nerve-derived mediators interfere with local immune responses. Thus, CGRP as an anti-inflammatory mediator could represent a new therapeutic tool in asthma therapy.
authors.affiliation: Department of Airway Immunology, Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Rochlitzer
authors.forename: T Z
authors.initials: TZ
authors.lastname: Veres
authors.forename: K
authors.initials: K
authors.lastname: Kühne
authors.forename: F
authors.initials: F
authors.lastname: Prenzler
authors.forename: C
authors.initials: C
authors.lastname: Pilzner
authors.forename: S
authors.initials: S
authors.lastname: Knothe
authors.forename: C
authors.initials: C
authors.lastname: Winkler
authors.forename: H-D
authors.initials: HD
authors.lastname: Lauenstein
authors.forename: M
authors.initials: M
authors.lastname: Willart
authors.forename: H
authors.initials: H
authors.lastname: Hammad
authors.forename: M
authors.initials: M
authors.lastname: Müller
authors.forename: N
authors.initials: N
authors.lastname: Krug
authors.forename: B N
authors.initials: BN
authors.lastname: Lambrecht
authors.forename: A
authors.initials: A
authors.lastname: Braun
mesh_terms: D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000378:metabolism; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000949:Histocompatibility Antigens Class II; D018015:Receptors, Calcitonin Gene-Related Peptide; D015740:Calcitonin Gene-Related Peptide