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Association of ORMDL3 with rhinovirus‐induced endoplasmic reticulum stress and type I Interferon responses in human leucocytes
Author(s) -
Liu Y.P.,
Rajamanikham V.,
Baron M.,
Patel S.,
Mathur S. K.,
Schwantes E. A.,
Ober C.,
Jackson D. J.,
Gern J. E.,
Lemanske R. F.,
Smith J. A.
Publication year - 2017
Publication title -
clinical and experimental allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 154
eISSN - 1365-2222
pISSN - 0954-7894
DOI - 10.1111/cea.12903
Subject(s) - rhinovirus , immunology , interferon , endoplasmic reticulum , biology , genotype , unfolded protein response , chemokine , plasmacytoid dendritic cell , cell type , cell , gene , medicine , dendritic cell , virus , inflammation , immune system , genetics
Summary Background Children with risk alleles at the 17q21 genetic locus who wheeze during rhinovirus illnesses have a greatly increased likelihood of developing childhood asthma. In mice, overexpression of the 17q21 gene ORMDL 3 leads to airway remodelling and hyperresponsiveness. However, the mechanisms by which ORMDL 3 predisposes to asthma are unclear. Previous studies have suggested that ORMDL 3 induces endoplasmic reticulum ( ER ) stress and production of the type I interferon ( IFN )‐regulated chemokine CXCL 10. Objective The purpose of this study was to determine the relationship between ORMDL 3 and rhinovirus‐induced ER stress and type I IFN in human leucocytes. Methods ER stress was monitored by measuring HSPA 5 , CHOP and spliced XBP 1 gene expression, and type I IFN by measuring IFNB 1 ( IFN ‐β) and CXCL 10 expression in human cell lines and primary leucocytes following treatment with rhinovirus. Requirements for cell contact and specific cell type in ORMDL 3 induction were examined by transwell assay and depletion experiments, respectively. Finally, the effects of 17q21 genotype on the expression of ORMDL 3 , IFNB 1 and ER stress genes were assessed. Results THP ‐1 monocytes overexpressing ORMDL 3 responded to rhinovirus with increased IFNB 1 and HSPA 5 . Rhinovirus‐induced ORMDL 3 expression in primary leucocytes required cell–cell contact, and induction was suppressed by plasmacytoid dendritic cell depletion. The degree of rhinovirus‐induced ORMDL 3 , HSPA 5 and IFNB 1 expression varied by leucocyte type and 17q21 genotype, with the highest expression of these genes in the asthma‐associated genotype. Conclusions and Clinical Relevance Multiple lines of evidence support an association between higher ORMDL 3 and increased rhinovirus‐induced HSPA 5 and type I IFN gene expression. These associations with ORMDL 3 are cell type specific, with the most significant 17q21 genotype effects on ORMDL 3 expression and HSPA 5 induction evident in B cells. Together, these findings have implications for how the interaction of increased ORMDL 3 and rhinovirus may predispose to asthma.