Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 42, Issue 2, Pages 393-402Publisher
WILEY
DOI: 10.1002/eji.201141845
Keywords
Animal models; Asthma; INF-gamma; Neurokinin
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Funding
- Ministry of Education, Culture, Sports, Science and Technology
- Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT)
- Institute for Genetic Medicine, Hokkaido University
- Grants-in-Aid for Scientific Research [22300331, 22700894, 22790370] Funding Source: KAKEN
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The adoptive transfer of OVA-specific Th1 cells into WT mice followed by OVA inhalation induces a significant elevation of airway hyper-responsiveness (AHR) with neutrophilia but not mucus hypersecretion. Here, we demonstrate that the airway inflammation model, pathogenically characterized as severe asthma, was partly mimicked by i.n. administration of IFN-gamma. The administration of IFN-gamma instead of Th1 cells caused AHR elevation but not neutrophilia, and remarkably induced neurokinin-2 receptor (NK2R) expression along with neurokinin A (NKA) production in the lung. To evaluate whether NKA/NK2R was involved in airway inflammation, we first investigated the role of NKA/NK2R-signaling in airway smooth muscle cells (ASMCs) in vitro. NK2R mRNA expression was significantly augmented in tracheal tube-derived ASMCs of WT mice but not STAT-1-/- mice after stimulation with IFN-gamma. In addition, methacholine-mediated Ca2+ influx into the ASMCs was significantly reduced in the presence of NK2R antagonist. Moreover, the NK2R antagonist strongly inhibited IFN-gamma-dependent AHR elevation in vivo. Thus, these results demonstrated that IFN-gamma directly acts on ASMCs to elevate AHR via the NKA/NK2R-signaling cascade. Our present findings suggested that NK2R-mediated neuro-immuno crosstalk would be a promising target for developing novel drugs in Th1-cell-mediated airway inflammation, including severe asthma.
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