NGF/TrkA-mediated Kidins220/ARMS signaling activated in the allergic airway challenge in mice

Abstract

Nerve growth factor (NGF), combined with its high-affinity receptor tyrosine kinase receptor A (TrkA), has been reported to be involved in the pathogenesis of asthma. To investigate whether the downstream protein ankyrin-rich membrane spanning (ARMS), a novel transmembrane substrate of protein kinase D (Kidins220), is activated in the pathogenesis of asthma. The asthmatic model was established by the inhalation of ovalbumin in BALB/c mice. The effects of NGF and TrkA on Kidins220/ARMS in an allergic airway challenge were assessed by administering anti-NGF or anti-TrkA antibody to the mice. Pathologic changes in the bronchi and lung tissues were examined by means of hematoxylin and eosin staining; the inflammatory cells in the bronchoalveolar lavage fluid (BALF) were counted; and co-expression of ARMS and TrkA in BALF cells was observed by means of immunofluorescence. In addition, Kidins220/ARMS, CrkL, NGF, TrkA protein, and Kidins220 messenger RNA levels were determined using Western blot or quantitative reverse transcription-polymerase chain reaction. Using fluorescence microscopy, we found that Kidins220 and TrkA were co-expressed on the membranes of the BALF cells of asthmatic mice. Compared with expression in control animals, Kidins220/ARMS, CrkL, NGF, and TrkA were overexpressed in the lungs after allergen challenge. Moreover, after the mice were treated with anti-NGF or anti-TrkA, the Kidins220/ARMS levels and allergen-induced airway inflammation decreased. These results suggest that Kidins220/ARMS partly participates in the pathogenesis of asthma through the NGF-TrkA signaling pathway, possibly representing a new mechanism in asthma.