Abstract
BackgroundOroscomucoid 3 (ORMDL3) has been linked to susceptibility of childhood asthma and respiratory viral infection. Polyinosinic-polycytidylic acid (poly I:C) is a synthetic analog of viral double-stranded RNA, a toll-like receptor 3 (TLR3) ligand and mimic of viral infection.MethodsTo investigate the functional role of ORMDL3 in the poly I:C-induced inflammatory response in airway epithelial cells, ORMDL3 knockdown and over-expression models were established in human A549 epithelial cells and primary normal human bronchial epithelial (NHBE) cells. The cells were stimulated with poly I:C or the Th17 cytokine IL-17A. IL-6 and IL-8 levels in supernatants, mRNA levels of genes in the TLR3 pathway and inflammatory response from cell pellets were measured. ORMDL3 knockdown models in A549 and BEAS-2B epithelial cells were then infected with live human rhinovirus (HRV16) followed by IL-6 and IL-8 measurement.ResultsORMDL3 knockdown and over-expression had little influence on the transcript levels of TLR3 in airway epithelial cells. Time course studies showed that ORMDL3-deficient A549 and NHBE cells had an attenuated IL-6 and IL-8 response to poly I:C stimulation. A549 and NHBE cells over-expressing ORMDL3 released relatively more IL-6 and IL-8 following poly I:C stimulation. IL-17A exhibited a similar inflammatory response in ORMDL3 knockdown and over-expressing cells, but co-stimulation of poly I:C and IL-17A did not significantly enhance the IL-6 and IL-8 response. Transcript abundance of IFNB following poly I:C stimulation was not significantly altered by ORMDL3 knockdown or over-expression. Dampening of the IL-6 response by ORMDL3 knockdown was confirmed in HRV16 infected BEAS-2B and A549 cells.ConclusionsORMDL3 regulates the viral inflammatory response in airway epithelial cells via mechanisms independent of the TLR3 pathway.
Highlights
Oroscomucoid 3 (ORMDL3) has been linked to susceptibility of childhood asthma and respiratory viral infection
We investigated the role of ORMDL3 in the host inflammatory response to viral stimulation, as mimicked by polyinosinic-polycytidylic acid, in airway epithelial cells
ORMDL3 does not impact baseline Toll-like receptor 3 (TLR3) expression in A549 cells TLR3 transcript abundance data were available as part of a prior global gene expression time course study of ORMDL3 knockdown and IL-1β stimulation in A549 cells [6]
Summary
Oroscomucoid 3 (ORMDL3) has been linked to susceptibility of childhood asthma and respiratory viral infection. Laura et al BMC Pulm Med (2021) 21:167 genome-wide association study (GWAS) of asthma identified single nucleotide polymorphisms (SNPs) flanking ORMDL3 gene on chromosome 17 to be significantly associated with the disease [1]. This association has subsequently been replicated in many studies worldwide, including a multi-ancestry global meta-analysis [2]. Chromosome 17 ORMDL3 locus is recognised as the major predisposing factor for childhood-onset asthma. Significant increases in the number of wheezing illnesses have been observed in children with enhanced transcription genotypes at the 17q21 ORMDL3 locus
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