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 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.
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.
Sung Gil
SG
Ha
Xiao Na
XN
Ge
Nooshin S
NS
Bahaie
Bit Na
BN
Kang
Amrita
A
Rao
Savita P
SP
Rao
P
P
Sriramarao
D008841:Actin Cytoskeleton / Q000187:drug effects; D000818:Animals; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D001249:Asthma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018821:CD18 Antigens / Q000235:genetics* / Q000378:metabolism; D000071178:CD48 Antigen; D002448:Cell Adhesion / Q000187:drug effects; D015550:Cell Degranulation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D048430:Cell Shape; D054413:Chemokine CCL11 / Q000494:pharmacology; D004804:Eosinophils / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D039441:Integrin alpha4 / Q000235:genetics* / Q000378:metabolism; D007377:Interleukin-3 / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D015703:Antigens, CD; D018821:CD18 Antigens; D000071178:CD48 Antigen; C515457:Ccl11 protein, mouse; C000604066:Cd48 protein, mouse; D054413:Chemokine CCL11; D007377:Interleukin-3; D008565:Membrane Proteins; D016328:NF-kappa B; C583840:ORMDL3 protein, mouse; D034741:RNA, Small Interfering; D039441:Integrin alpha4; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3