Ormdl3-LacZ reporter mice, gene-deficient Ormdl3<sup>-/-</sup> mice, and overexpressing Ormdl3<sup>Tg/wt</sup> mice were exposed to physiologically relevant aeroallergens, such as house dust mite (HDM) or Alternaria alternata, to induce experimental asthma.
We also suggest a potential unifying paradigm and discuss molecular mechanisms for the pathologic functions of ORMDL3 in asthma related to its evolutionarily conserved role in regulation of sphingolipid homeostasis.
This study aimed to investigate whether the p300-mediated histone acetylation (HAT) of ORMDL3 gene affects airway inflammation and remodeling in asthma.
Increased orosomucoid-like 3 (ORMDL3) expression levels, due to single nucleotide polymorphisms (SNPs), have been associated with several inflammatory diseases, including asthma and inflammatory bowel diseases.
Collectively, our results demonstrate that the ORMDL3 gene may aggravate asthma symptoms by activating the JNK1/2-MMP-9 pathway, which indicates that the ORMDL3 gene may be the key molecule for the next step of asthma targeted therapy.
We investigated whether increased ASM expression of orosomucoid-like 3 (ORMDL3), a gene on chromosome 17q21 highly linked to asthma, induced increased ASM proliferation and contractility in vitro and influenced airway contractility and calcium flux in ASM in precision-cut lung slices (PCLSs) from wild-type and hORMDL3<sup>Zp3-Cre</sup> mice (which express increased levels of human ORMDL3 [hORMDL3]).
We review 10 years of studies on the 17q12-21 locus and suggest that genotype-specific risks for asthma at the proximal and distal loci are not specific to early-onset asthma and mediated by PGAP3, ORMDL3, and/or GSDMA expression.
The present study attempted to examine the associations between ORMDL3 and the severity of airway remodeling in asthmatic mice, and also to determine whether ORMDL3 induces epithelial‑mesenchymal transition (EMT) in the bronchial epithelium.
PCR analysis confirmed significantly increased Ca<sup>2+</sup> -associated gene regulation (ORMDL3 and ATP2A3) in asthmatics vs HC, most prominent in AA.
A growing body of evidence has suggested the genetic association of ORMDL3 gene (ORMDL Sphingolipid Biosynthesis Regulator 3) polymorphisms with a diverse set of inflammatory disorders that include bronchial asthma, inflammatory bowel disease, ankylosing spondylitis and atherosclerosis.
This study demonstrates that ORMDL3, an asthma susceptibility gene identified by genome-wide association studies, contributes to key pathways that promote changes in airway physiology during allergic immune responses.
Addition of myriocin during sensitization drastically exacerbates house dust mites-induced AHR.ORMDL3 knockout mice are protected from developing A. alternata-induced AHR.
As the single nucleotide polymorphisms linking ORMDL3 to asthma are associated with increased expression of ORMDL3, we have used hORMDL3<sup>zp3-Cre</sup> mice (which have universal increased expression of human ORMDL3) to determine whether infection of these transgenic mice with RV influences levels of airway inflammation or RV viral load.
Chromosomal region 17q12-q21 is associated with asthma and harbors regulatory polymorphisms that influence expression levels of all five protein-coding genes in the region: IKAROS family zinc finger 3 (Aiolos) (IKZF3), zona pellucida binding protein 2 (ZPBP2), ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3), and gasdermins A and B (GSDMA, GSDMB).
Expression levels of ORMDL3, phosphorylated (p)‑ERK and MMP‑9 were significantly greater in the asthma‑model group; however, in the group pretreated with budesonide their expression was reduced.
The first GWAS was published in 2007, and described a new locus associated to asthma in chromosome 17q12-q21, involving the ORMDL3, GSDMB and ZPBP2 genes (a description of the genes named in the manuscript are listed in Table 1).
Asthma and autoimmune disease susceptibility has been strongly linked to genetic variants in the 17q21 haploblock that alter the expression of ORMDL3; however, the molecular mechanisms by which these variants perturb gene expression and the cell types in which this effect is most prominent are unclear.