Exp Mol Med.  2018 Feb;50(2):e444. 10.1038/emm.2017.270.

PI3Kδ contributes to ER stress-associated asthma through ER-redox disturbances: the involvement of the RIDD–RIG-I–NF-κB axis

• Kim HK
• Lee GH
• Bhattarai
• Junjappa R
• Lee HY
• Handigund
• Marahatta
• Bhandary B
• Baek IH
• Pyo JS
• Kim HK
• Chai OH
• Kim HR
• Lee YC
• Chae HJ

• KMID: 2440026
• DOI: http://doi.org/10.1038/emm.2017.270

Abstract

Hyperactivation of phosphoinositol 3-kinase (PI3K) has been suggested to be a potential mechanism for endoplasmic reticulum (ER) stress-enhanced airway hyperresponsiveness, and PI3K inhibitors have been examined as asthma therapeutics. However, the regulatory mechanism linking PI3K to ER stress and related pathological signals in asthma have not been defined. To elucidate these pathogenic pathways, we investigated the influence of a selective PI3Kδ inhibitor, IC87114, on airway inflammation in an ovalbumin/lipopolysaccharide (OVA/LPS)-induced asthma model. In OVA/LPS-induced asthmatic mice, the activity of PI3K, downstream phosphorylation of AKT and activation of nuclear factor-κB (NF-κB) were all significantly elevated; these effects were reversed by IC87114. IC87114 treatment also reduced the OVA/LPS-induced ER stress response by enhancing the intra-ER oxidative folding status through suppression of protein disulfide isomerase activity, ER-associated reactive oxygen species (ROS) accumulation and NOX4 activity. Furthermore, inositol-requiring enzyme-1α (IRE1α)-dependent degradation (RIDD) of IRE1α was reduced by IC87114, resulting in a decreased release of proinflammatory cytokines from bronchial epithelial cells. These results suggest that PI3Kδ may induce severe airway inflammation and hyperresponsiveness by activating NF-κB signaling through ER-associated ROS and RIDD-RIG-I activation. The PI3Kδ inhibitor IC87114 is a potential therapeutic agent against neutrophil-dominant asthma.

MeSH Terms

Animals
Asthma*
Cytokines
Endoplasmic Reticulum
Epithelial Cells
Inflammation
Mice
Phosphorylation
Protein Disulfide-Isomerases
Reactive Oxygen Species
Cytokines
Protein Disulfide-Isomerases
Reactive Oxygen Species