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

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 IL-3 and eotaxin-1. Over-expression of ORMDL3 in eosinophils causes increased rolling, distinct cytoskeletal rearrangement, ERK (1/2) phosphorylation and nuclear translocation of NF-κB. Knock-down 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. Additionally, ORMDL3 regulates IL-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.