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

• Published in: Experimental & molecular medicine 2018-02, Vol.50 (2), p.e444-e444
• Main Authors: Kim, Hyun-Kyoung, Lee, Geum-Hwa, Bhattarai, Kashi Raj, Junjappa, Raghu Patil, Lee, Hwa-Young, Handigund, Mallikarjun, Marahatta, Anu, Bhandary, Bidur, Baek, In-Hwan, Pyo, Jae Sung, Kim, Hye-Kyung, Chai, Ok Hee, Kim, Hyung-Ryong, Lee, Yong-Chul, Chae, Han-Jung
• Format: Article
• Language: English
• Subjects: 13/51; 14/19; 38/77; 38/90; 59; 631/250/347; 631/337/470/1463; 64/60; 82/29; 82/51; Adenine - analogs & derivatives; Adenine - pharmacology; Animals; Asthma - etiology; Asthma - metabolism; Biomedical and Life Sciences; Biomedicine; Disease Models, Animal; Endoplasmic Reticulum Stress - drug effects; Lipid Peroxidation; Lipopolysaccharides - immunology; Medical Biochemistry; Membrane Proteins - metabolism; Mice; Molecular Medicine; Nerve Tissue Proteins - metabolism; NF-kappa B - metabolism; Original; original-article; Ovalbumin - immunology; Oxidation-Reduction; Oxidative Stress - drug effects; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; Quinazolines - pharmacology; Reactive Oxygen Species - metabolism; Signal Transduction - drug effects; Stem Cells
• ISSN: 1226-3613; 2092-6413
• DOI: 10.1038/emm.2017.270

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. Asthma: Inflammation-blocking drug relieves intracellular stress A pro-inflammatory protein induces asthma by stressing the endoplasmic reticulum (ER), the cell organelle responsible for protein folding. Drugs that block this stress could help treat asthma. A team led by Han-Jung Chae from Chonbuk National University in Jeonju, South Korea, examined the molecular effects of treating a mouse model of asthma with an aerosolized drug that inhibits phosphoinositol 3-kinase (PI3K), a protein involved in regulating immune mediators of inflammation. The researchers found that blocking PI3K activity led to lower levels of misfolded proteins and toxic free radicals in the ER. Consequently, cells lining the inside of the lungs released fewer pro-inflammatory signaling molecules, and the mice were less sensitive to asthma triggers. The authors conclude that inhalable PI3K inhibitors could help treat severe asthma.