Cutting edge: Targeting epithelial ORMDL3 increases, rather than reduces, airway responsiveness and is associated with increased sphingosine-1-phosphate

Marina Miller, Arvin B. Tam, James L. Mueller, Peter Rosenthal, Andrew Beppu, Ruth Gordillo, Matthew D. McGeough, Christine Vuong, Taylor A. Doherty, Hal M. Hoffman, Maho Niwa, David H. Broide

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

In this study, we used cre-lox techniques to generate mice selectively deficient in ORMDL3 in airway epithelium (Ormdl3Δ2-3/Δ2-3/CC10) to simulate an inhaled therapy that effectively inhibited ORMDL3 expression in the airway. In contrast to the anticipated reduction in airway hyperresponsiveness (AHR), OVA allergen-challenged Ormdl3Δ2-3/Δ2-3/CC10 mice had a significant increase in AHR compared with wild-type mice. Levels of airway inflammation, mucus, fibrosis, and airway smooth muscle were no different in Ormdl3Δ2-3/Δ2-3/CC10 and wild-type mice. However, levels of sphingosine-1-phosphate (S1P) were significantly increased in Ormdl3Δ2-3/Δ2-3/CC10 mice as well as in airway epithelial cells in which ORMDL3 was inhibited with small interfering RNA. Incubation of S1P with airway smooth muscle cells significantly increased contractility. Overall, Ormdl3Δ2-3/Δ2-3/CC10 mice exhibit increased allergen-induced AHR independent of inflammation and associated with increased S1P generation. These studies raise concerns for inhaled therapies that selectively and effectively inhibit ORMDL3 in airway epithelium in asthma.

Original languageEnglish (US)
Pages (from-to)3017-3022
Number of pages6
JournalJournal of Immunology
Volume198
Issue number8
DOIs
StatePublished - Apr 15 2017

ASJC Scopus subject areas

  • Immunology

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    Miller, M., Tam, A. B., Mueller, J. L., Rosenthal, P., Beppu, A., Gordillo, R., McGeough, M. D., Vuong, C., Doherty, T. A., Hoffman, H. M., Niwa, M., & Broide, D. H. (2017). Cutting edge: Targeting epithelial ORMDL3 increases, rather than reduces, airway responsiveness and is associated with increased sphingosine-1-phosphate. Journal of Immunology, 198(8), 3017-3022. https://doi.org/10.4049/jimmunol.1601848