Eosinophil peroxidase induces the expression and function of acid‐sensing ion channel‐3 in allergic rhinitis: in vitro evidence in cultured epithelial cells

• DOI: 10.1111/j.1365-2222.2012.03980.x
• Publication Date: 2012-02-14T15:35:34Z
• Authors: S. G. Khoo; M. Al‐Alawi; M. T. Walsh; K. Hennigan; S. Glynn; M. Thornton; S. McQuaid; Y. Wang; P. W. Hamilton; V. Verriere; G. J. Gleich; B. J. Harvey; R. W. Costello; L. P. McGarvey
• Keywords: Adult; Male; 0301 basic medicine; Eosinophil Peroxidase; Adolescent; MAP Kinase Signaling System; Biopsy; 610; Polymerase Chain Reaction; Sodium Channels; 03 medical and health sciences; /dk/atira/pure/subjectarea/asjc/2700/2723; Humans; name=Immunology; Lactic Acid; /dk/atira/pure/subjectarea/asjc/2400/2403; Cells, Cultured; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Rhinitis, Allergic, Seasonal; Epithelial Cells; 3. Good health; name=Immunology and Allergy; Acid Sensing Ion Channels; Nasal Mucosa; Gene Expression Regulation; Female

SummaryBackgroundAcid‐sensing ion channels (ASIC) are a family of acid‐activated ligand‐gated cation channels. As tissue acidosis is a feature of inflammatory conditions, such as allergic rhinitis (AR), we investigated the expression and function of these channels in AR.ObjectivesThe aim of the study was to assess expression and function of ASIC channels in the nasal mucosa of control and AR subjects.MethodsImmunohistochemical localization of ASIC receptors and functional responses to lactic acid application were investigated. In vitro studies on cultured epithelial cells were performed to assess underlying mechanisms of ASIC function.ResultsLactic acid at pH 7.03 induced a significant rise in nasal fluid secretion that was inhibited by pre‐treatment with the ASIC inhibitor amiloride in AR subjects (n = 19). Quantitative PCR on cDNA isolated from nasal biopsies from control and AR subjects demonstrated that ASIC‐1 was equally expressed in both populations, but ASIC‐3 was significantly more highly expressed in AR (P < 0.02). Immunohistochemistry confirmed significantly higher ASIC‐3 protein expression on nasal epithelial cells in AR patients than controls (P < 0.01). Immunoreactivity for EPO+ eosinophils in both nasal epithelium and submucosa was more prominent in AR compared with controls. A mechanism of induction of ASIC‐3 expression relevant to AR was suggested by the finding that eosinophil peroxidase (EPO), acting via ERK1/2, induced the expression of ASIC‐3 in epithelial cells. Furthermore, using a quantitative functional measure of epithelial cell secretory function in vitro, EPO increased the air‐surface liquid depth via an ASIC‐dependent chloride secretory pathway.ConclusionsThis data suggests a possible mechanism for the observed association of eosinophils and rhinorrhoea in AR and is manifested through enhanced ASIC‐3 expression.