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J Immunol. 2017 Apr 15;198(8):3017-3022. doi: 10.4049/jimmunol.1601848. Epub 2017 Mar 8.

Cutting Edge: Targeting Epithelial ORMDL3 Increases, Rather than Reduces, Airway Responsiveness and Is Associated with Increased Sphingosine-1-Phosphate.

Author information

1
Department of Medicine, University of California, San Diego, La Jolla, CA 92093.
2
Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093.
3
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093; and.
4
Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390.
5
Department of Medicine, University of California, San Diego, La Jolla, CA 92093; dbroide@ucsd.edu.

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.

PMID:
28275141
PMCID:
PMC5399887
DOI:
10.4049/jimmunol.1601848
[Indexed for MEDLINE]
Free PMC Article

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