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Nat Commun. 2013;4:2479. doi: 10.1038/ncomms3479.

ORMDL3 promotes eosinophil trafficking and activation via regulation of integrins and CD48.

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1
Laboratory of Allergic Diseases and Inflammation, Departments of Veterinary and Biomedical Sciences and Medicine, University of Minnesota, 1971 Commonwealth Avenue, St Paul, Minnesota 55108, USA.

Abstract

ORM (yeast)-like protein isoform 3 (ORMDL3) has recently been identified as a candidate gene for susceptibility to asthma; however, the mechanisms by which it contributes to asthma pathogenesis are not well understood. Here we demonstrate a functional role for ORMDL3 in eosinophils in the context of allergic inflammation. Eosinophils recruited to the airways of allergen-challenged mice express ORMDL3. ORMDL3 expression in bone marrow eosinophils is localized in the endoplasmic reticulum and is induced by interleukin-3 and eotaxin-1. Overexpression of ORMDL3 in eosinophils causes increased rolling, distinct cytoskeletal rearrangement, extracellular signal-regulated kinase (1/2) phosphorylation and nuclear translocation of nuclear factor kappa B. Knockdown of ORMDL3 significantly inhibits activation-induced cell shape changes, adhesion and recruitment to sites of inflammation in vivo, combined with reduced expression of CD49d and CD18. In addition, ORMDL3 regulates interleukin-3-induced expression of CD48 and CD48-mediated eosinophil degranulation. These studies show that ORMDL3 regulates eosinophil trafficking, recruitment and degranulation, further elucidating a role for this molecule in allergic asthma and potentially other eosinophilic disorders.

PMID:
24056518
PMCID:
PMC3940275
DOI:
10.1038/ncomms3479
[Indexed for MEDLINE]
Free PMC Article

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