Prenatal LPS Exposure Promotes Allergic Airway Inflammation via Long Coding RNA NONMMUT033452.2, and Protein Binding Partner, Eef1D.

Epidemiological surveys indicate that intrauterine inflammation increases the risk of asthma in the offspring. However, the underlying mechanisms remain largely unknown. Previous studies in BALB/c and C57BL/6 mice showed that prenatal exposure to endotoxins prevented offspring allergic airway inflammation, which is inconsistent with most clinical observations. In this study, we found that prenatal lipopolysaccharide (LPS) exposure increased the airway resistance and total exfoliated cell counts, eosinophils, and interleukin (IL)-4 levels in the bronchoalveolar lavage fluid of ovalbumin-sensitized ICR mice. Importantly, lncRNA NONMMUT033452.2 was upregulated in the lungs of LPS-exposed ICR offspring. Fluorescence in situ hybridization and cytoplasmic-nuclear fraction analyses revealed that this lncRNA was distributed in both the nuclei and cytoplasm of lung and airway epithelial cells, smooth muscle cells, and fibroblasts. Intranasal administration of NONMMUT033452.2 siRNA markedly alleviated allergic airway inflammation in the ovalbumin-sensitized ICR mice. In vitro functional experiments demonstrated that overexpression of NONMMUT033452.2 inhibited the proliferation of lung and bronchiolar epithelial cells and promoted oxidative stress. RNA pull-down assays proved that NONMMUT033452.2 could directly bind Eef1D. Overexpression of NONMMUT033452.2 induced the redistribution of Eef1D and substantially inhibited the expression of its downstream heat-shock genes. NONMMUT033452.2 was also involved in the modulation of IL-1, IL-12 and some key molecules related to asthma, including Npr3, Rac1 and Nr4a3. Furthermore, the human lncRNA NONHSAT078603.2 was identified to be a functional homolog of NONMMUT033452.2. The findings provide new insight into the pathogenic mechanism underlying asthma development.