Open AccessPI3Kδ contributes to ER stress-associated asthma through ER-redox disturbances: the involvement of the RIDD–RIG-I–NF-κB axis
Author(s) -
Mi Kyeong Kim,
Keum Hwa Lee,
Kashi Raj Bhattarai,
Raghu Patil Junjappa,
Hwa Young Lee,
Mallikarjun Handigund,
Anu Marahatta,
Bidur Bhandary,
Inhwan Baek,
Jae Sung Pyo,
Hye Kyung Kim,
Ok Hee Chai,
Hyung Ryong Kim,
Yong Chul Lee,
Han-Jung Chae
Publication year - 2018
Publication title -
experimental and molecular medicine/experimental and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.703
H-Index - 82
eISSN - 2092-6413
pISSN - 1226-3613
DOI - 10.1038/emm.2017.270
Subject(s) - unfolded protein response , endoplasmic reticulum , pi3k/akt/mtor pathway , proinflammatory cytokine , protein kinase b , oxidative stress , ovalbumin , inflammation , chemistry , phosphorylation , signal transduction , cancer research , microbiology and biotechnology , immunology , medicine , biology , biochemistry , immune system
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.