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

Sung Gil Ha, Xiaona Ge, Nooshin S. Bahaie, Bit Na Kang, Amrita Rao, Savita P Rao, Srirama Rao

Research output: Contribution to journalArticlepeer-review

64 Scopus citations

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.

Original languageEnglish (US)
Article number2479
JournalNature communications
Volume4
DOIs
StatePublished - 2013

Bibliographical note

Funding Information:
The authors wish to thank Yana Greenberg for excellent technical assistance. This work was supported by NIH Grant no. HL108000 and AI35796 to P.S.

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