Imperial College London
Alternate

ProfessorClareLloyd

Faculty of Medicine, National Heart & Lung Institute

Interim Head of NHLI, Vice-Dean (institutional Affairs) FoM
 
 
 
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Contact

 

+44 (0)20 7594 3102c.lloyd Website

 
 
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Location

 

Office 352Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{Zhang:2019:10.1164/rccm.201803-0438OC,
author = {Zhang, Y and Willis-Owen, S and Spiegel, S and Lloyd, C and Moffatt, M and Cookson, W},
doi = {10.1164/rccm.201803-0438OC},
journal = {American Journal of Respiratory and Critical Care Medicine},
pages = {478--488},
title = {The ORMDL3 asthma gene regulates ICAM1 and has multiple effects on cellular inflammation},
url = {http://dx.doi.org/10.1164/rccm.201803-0438OC},
volume = {199},
year = {2019}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Rationale: Polymorphisms on chromosome 17q21 confer the major genetic susceptibility to childhood-onset asthma. Risk alleles positively correlate with ORMDL3 expression. The locus influences disease severity and the frequency of human rhinovirus (HRV) initiated exacerbations. ORMDL3 is known to regulate sphingolipid synthesis by binding serine palmitoyltransferase (SPT), but its role in inflammation is incompletely understood. Objectives: To investigate the role of ORMDL3 in cellular inflammation. Methods: We modelled time-series of IL1B-induced inflammation in A549 cells, using cytokine production as outputs and testing effects of ORMDL3 siRNA knockdown, ORMDL3 overexpression, and the SPT inhibitor myriocin. We replicated selected findings in normal human bronchial epithelial (NHBE) cells. Cytokine and metabolite levels were analysed by ANOVA. Transcript abundances were analysed by group means parameterisation, controlling the false discovery rate (FDR) below 0.05. Measurements and Main Results: Silencing ORMDL3 led to steroid-independent reduction of IL6 and IL8 release and reduced ER stress after IL1B. Overexpression and myriocin conversely augmented cytokine release. Knockdown reduced expression of genes regulating host-pathogen interactions, stress responses and ubiquitination: in particular ORMDL3 knockdown strongly reduced expression of the HRV receptor ICAM1. Silencing led to changes in levels of transcripts and metabolites integral to glycolysis. Increased levels of ceramides and the immune mediator sphingosine-1-P (S1P) were also observed. Conclusions: The results show ORMDL3 has pleiotropic effects during cellular inflammation, consistent with its substantial genetic influence on childhood asthma. Actions on ICAM1 provide a mechanism for the locus to confer susceptibility to HRV-induced asthma.
AU  - Zhang,Y
AU  - Willis-Owen,S
AU  - Spiegel,S
AU  - Lloyd,C
AU  - Moffatt,M
AU  - Cookson,W
DO  - 10.1164/rccm.201803-0438OC
EP  - 488
PY  - 2019///
SN  - 1073-449X
SP  - 478
TI  - The ORMDL3 asthma gene regulates ICAM1 and has multiple effects on cellular inflammation
T2  - American Journal of Respiratory and Critical Care Medicine
UR  - http://dx.doi.org/10.1164/rccm.201803-0438OC
UR  - https://www.atsjournals.org/doi/10.1164/rccm.201803-0438OC
UR  - http://hdl.handle.net/10044/1/65625
VL  - 199
ER  -
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