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Published on: January 7, 2019
ORMDL3 regulates poly I:C induced inflammatory responses in airway epithelial cells
Gemma Laura1, Yi Liu1, Kieran Fernandes1
1National Heart and Lung Institute, Imperial College London, London, SW3 6LY, UK.
Background:
Oroscomucoid 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.
Methods:
To 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.
Results:
ORMDL3 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.
Conclusions:
ORMDL3 regulates the viral inflammatory response in airway epithelial cells via mechanisms independent of the TLR3 pathway.
Insights
Orosmucoid 3 (ORMDL3) regulates airway epithelial cell inflammatory responses to viral infections. ORMDL3 deficiency reduces IL-6 and IL-8 production following poly I:C or rhinovirus stimulation, independent of TLR3 signaling.
Area of Science:
- Immunology
- Respiratory Medicine
- Cell Biology
Background:
- Orosmucoid 3 (ORMDL3) is associated with childhood asthma and viral respiratory infections.
- Polyinosinic-polycytidylic acid (poly I:C) mimics viral double-stranded RNA and activates Toll-like receptor 3 (TLR3).
Purpose of the Study:
- To investigate the role of ORMDL3 in the inflammatory response of airway epithelial cells induced by poly I:C.
- To determine if ORMDL3 influences inflammatory cytokine production during viral infections.
Main Methods:
- Established ORMDL3 knockdown and over-expression models in human A549 and primary normal human bronchial epithelial (NHBE) cells.
- Stimulated cells with poly I:C or IL-17A, and measured IL-6 and IL-8 levels.
- Infected ORMDL3-deficient cells with human rhinovirus (HRV16) and assessed inflammatory markers.
Main Results:
- ORMDL3 modulation minimally affected TLR3 transcript levels.
- ORMDL3 deficiency attenuated IL-6 and IL-8 responses to poly I:C and HRV16.
- ORMDL3 over-expression increased IL-6 and IL-8 release after poly I:C stimulation.
Conclusions:
- ORMDL3 plays a regulatory role in the viral inflammatory response in airway epithelial cells.
- This regulation occurs through mechanisms independent of the TLR3 pathway.
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