Age dictates a steroid resistant cascade of Wnt5a, transglutaminase-2 and leukotrienes in inflamed airways

Publication date: Available online 20 August 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Katharina Dietz, Marta de los Reyes Jiménez, Eva S. Gollwitzer, Adam M. Chaker, Ulrich M. Zissler, Olof P. Rådmark, Hoeke A. Baarsma, Melanie Königshoff, Carsten B. Schmidt-Weber, Benjamin J. Marsland, Julia Esser-von Bieren
BackgroundAirway remodeling is a detrimental and refractory process showing age-dependent clinical manifestations, which are mechanistically undefined. The leukotriene (LT) and wingless/ integrase (Wnt) pathways have been implicated in remodeling, but age-specific expression profiles and common regulators remained elusive.ObjectiveWe sought to study the activation of the LT and Wnt pathways during early- or late-onset allergic airway inflammation and to address regulatory mechanisms and clinical relevance in normal human bronchial epithelial cells (NHBEs) and nasal polyp tissues.MethodsMice were sensitized with house dust mite allergens (HDM) from day 3, 15 or 60 after birth. Remodeling factors in murine bronchoalveolar lavage fluid (BALF), lung or human nasal polyp tissues were analyzed by westernblot, immunoassays or histology. Regulatory mechanisms were studied in cytokine/HDM- stimulated NHBEs and macrophages.ResultsBALF LT levels were increased in neonatal and adult, but reduced in juvenile HDM-sensitized mice. Lungs of neonatally-sensitized mice showed increased 5-lipoxygenase levels, whilst adult mice expressed more secretory phospholipase A2 (sPLA2-X), Wnt5a and transglutaminase 2 (TGM2). Older mice showed co-localization of Wnt5a and LT enzymes in the epithelium, a pattern also observed in human nasal polyps. IL-4 promoted epithelial Wnt5a secretion, which upregulated macrophage TGM2 expression and TGM2 inhibition in turn reduced LT release. TGM2, sPLA2-X and LT enzymes in NHBEs and nasal polyps were refractory to corticosteroids.ConclusionOur findings reveal age differences in LT and Wnt pathways during airway inflammation and identify a steroid-resistant cascade of Wnt5a, TGM2 and LTs, which may represent a therapeutic target for airway inflammation and remodeling.

Teaser

Epithelial remodeling factors are differentially regulated during early- and late-onset allergic airway inflammation. Age-specific diagnostic, preventive and therapeutic approaches may thus be required to improve the clinical outcomes for patients suffering from chronic airway inflammation.


from #ENT via xlomafota13 on Inoreader http://ift.tt/2b76Im7
via IFTTT