Abstract
Asthmatics with poor steroid responsiveness are now found to use health services at higher frequency and contribute to socio-economic burden disproportionately. We have previously shown that a ω-6 fatty acid metabolite leads to a severe and steroid insensitive asthma-like condition in mice. Here, we investigated the role of retinoid-x-receptor gamma (RXRγ) and Docosahexaenoic acid (DHA), a ω3 fatty acid rexinoid ligand of RXR, on the features of steroid insensitivity in asthmatic condition. RXRγ was found to be reduced in the lungs of human asthmatics and mice with steroid insensitive allergic airway inflammation. RXRγ knockdown in naïve mice led to spontaneous asthma like features whereas RXRγ knockdown in allergic mice led to steroid insensitive asthma features. We observed while RXRγ binds to the glucocorticoid receptor (GR) gene and regulates its transcription, DHA increases the GRα expression in human bronchial epithelial cells and reverses the steroid insensitive features in mice with allergic airway inflammation. Docosahexaenoic acid (DHA), a ligand of RXR, was reduced in the sera of steroid-insensitive asthmatics. We conclude that DHA may prove to be a promising steroid sensitizing agent for the treatment of steroid insensitive asthmatics.
Summary The molecular regulation of glucocorticoid receptor by retinoid-x-receptor gamma (RXRgama) has an implication in steroid insensitive asthma as we found that Docosahexaenoic acid (DHA), a nutritional supplement and natural ligand of RXRgamma, improves steroid sensitivity in steroid insensitive mice model of asthma and DHA levels are found to be low in steroid insensitive asthmatic patients.
Competing Interest Statement
The authors have declared no competing interest.
Abbreviations used
- AAI
- Allergic airway inflammation
- AHR
- Airway hyper-responsiveness
- ATRA
- All-trans retinoic acid
- AU
- Arbitrary units
- BAL
- Bronchoalveolar lavage
- BEAS-2B
- Human bronchial epithelial cells
- CE
- Cockroach allergen extract
- ChIP
- Chromatin Immunoprecipitation
- 9CRA
- 9-cis retinoic acid
- DEX
- Dexamethasone
- DHA
- Docosahexaenoic acid
- DMSO
- Dimethyl sulfoxide
- ELISA
- Enzyme-linked immunosorbent assay
- GAPDH
- Glyceraldehyde 3-phosphate dehydrogenase
- GLuc
- Gaussia luciferase
- GRα
- Glucocorticoid receptor alpha
- GRE
- Glucocorticoid receptor element
- H & E
- Haematoxylin and eosin
- IFNγ
- Interferon gamma
- IgE
- Immunoglobulin
- E IL
- Interleukin
- KC
- Keratinocyte chemoattractant
- 15-LOX
- 15-lipoxygenase
- MCF-7
- Human breast adenocarcinoma cell line
- MCP1-α
- Monocyte chemoattractant protein1-α
- NF-κB
- Nuclear Factor kappa-light-chain-enhancer of activated B cells
- O.E
- Overexpression
- OVA
- Ovalbumin
- p38-MAPK
- p38 mitogen-activated protein kinase
- PBS
- Phosphate buffered saline
- RAR
- Retinoic acid receptor
- PDTC
- Pyrrolidinedithiocarbamate
- RXRE
- Rexinoid receptor element
- RXRγ
- Retinoid-x-receptor gamma
- 13-S-HODE
- 13-hydroxyoctadecadienoic acid
- SEM
- Standard error mean
- siRNA
- Small interfering RNA
- STAT-6
- Signal transducer and activator of transcription 6
- Th
- T helper
- VEH
- Vehicle