Attenuation of antigen-induced airway hyperresponsiveness in CGRP-deficient mice

Abstract

Bronchial hyperresponsiveness and eosinophilia are major characteristics of asthma. Calcitonin gene-related peptide (CGRP) is a neuropeptide that has various biological actions. In the present study, we questioned whether CGRP might have pathophysiological roles in airway hyperresponsiveness and eosinophilia in asthma. To determine the exact roles of endogenous CGRP in vivo, we chose to study antigen-induced airway responses using CGRP gene-disrupted mice. After ovalbumin sensitization and antigen challenge, we assessed airway responsiveness and measured proinflammatory mediators. In the sensitized CGRP gene-disrupted mice, antigen-induced bronchial hyperresponsiveness was significantly attenuated compared with the sensitized wild-type mice. Antigen challenge induced eosinophil infiltration in bronchoalveolar lavage fluid, whereas no differences were observed between the wild-type and CGRP-mutant mice. Antigen-induced increases in cysteinyl leukotriene production in the lung were significantly reduced in the CGRP-disrupted mice. These findings suggest that CGRP could be involved in the antigen-induced airway hyperresponsiveness, but not eosinophil infiltration, in mice. The CGRP-mutant mice may provide appropriate models to study molecular mechanisms underlying CGRP-related diseases.

Calcitonin Gene-Related Peptide and Cyclic Adenosine 5′-Monophosphate/Protein Kinase A Pathway Promote IL-9 Production in Th9 Differentiation Process

“…These results suggest that CGRP receptor signaling is necessary for promoting airway inflammation. It has been reported that aCGRP-deficient mice also show resistance to airway inflammation, but that the IgE levels and number of eosinophils in BALF do not change (35). Consistent with this observation, serum IgE levels made no difference in wild-type and RAMP1-deficient mice in our experiments (Fig.…”

“…However, both Th0 and Th9 cells do not express calcitonin receptor, and recombinant calcitonin did not affect the production of IL-9 in vitro (data not shown). Moreover, in airway inflammation, the phenotype of aCGRPdeficient mice is similar with that of RAMP1-deficient mice (35). Therefore, these results strongly suggest that CGRP/CGRP receptor signaling promotes Th9 cell differentiation through upregulation of IL-9 production, which enhances IL-9-mediated inflammation.…”

“…Our investigations also showed that RAMP1-deficient mice were resistant to OVA-induced food allergy, although the regulatory mechanism has not been revealed (34). Moreover, it is reported that aCGRP-deficient mice exhibit less airway inflammation (35). Therefore, CGRP may be a physiological molecule that promotes type I hypersensitivity, and it is possible that CGRP promotes these inflammations by promoting Th9 cell functions.…”

“…It has been reported that airway inflammation is regulated by several GPCR ligands, such as CGRP, pituitary adenylate cyclase-activating polypeptide (PACAP), and vasoactive intestinal peptide (VIP) (35,54,55). Aoki-Nagase et al (35) demonstrated that aCGRP promotes airway inflammation using aCGRP-deficient mice, and our study also demonstrated that RAMP1-deficient mice show a decrease in the number of cells infiltrating into the lung due to a low level of IL-9 production compared with wild-type mice. These data suggest that CGRP physiologically promotes airway inflammation by accelerating the effects on Th9 cell differentiation and IL-9 production.…”

The GPCR modulator protein RAMP2 is essential for angiogenesis and vascular integrity

“…Thus, AM is now recognized to be a pleiotropic vasoactive molecule. To better understand the in vivo functions of AM, we established and analyzed genetically engineered AMdeficient mice (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Homozygous AM KO (AM -/-) mice die in utero at around midgestation from systemic hemorrhage and edema resulting from the fragility of their vasculature (14).…”