Phosphatidylinositol 3-kinase-δ controls endoplasmic reticulum membrane fluidity and permeability in fungus-induced allergic inflammation in mice

Phosphatidylinositol 3-kinase (PI3K), especially PI3K-δ, and endoplasmic reticulum (ER) stress play important roles in refractory asthma induced by the fungus Aspergillus fumigatus through mechanisms that are not well understood. Here we have investigated these mechanisms, using BEAS-2B human bronchial epithelial cells and a mouse model of A. fumigatus-induced allergic lung inflammation. Experimental approach: A selective PI3K-δ inhibitor, IC87114, and an ER folding chaperone, 4-phenylbutyric acid (4-PBA), were applied to a model of A. fumigatus-induced asthma in female C57BL/6 mice. The therapeutic potential of IC87114 and 4-PBA was assessed in relevant primary cell, tissue, and disease models, using immunohistochemistry, western blotting and assessment of ER redox state and membrane fluidity. Key

Phosphatidylinositol 3-kinase (PI3K), especially PI3K-δ, and endoplasmic reticulum (ER) stress play important roles in refractory asthma induced by the fungus Aspergillus fumigatus through mechanisms that are not well understood. Here we have investigated these mechanisms, using BEAS-2B human bronchial epithelial cells and a mouse model of A. fumigatus-induced allergic lung inflammation. Experimental approach: A selective PI3K-δ inhibitor, IC87114, and an ER folding chaperone, 4-phenylbutyric acid (4-PBA), were applied to a model of A. fumigatus-induced asthma in female C57BL/6 mice. The therapeutic potential of IC87114 and 4-PBA was assessed in relevant primary cell, tissue, and disease models, using immunohistochemistry, western blotting and assessment of ER redox state and membrane fluidity. Key

Treatment with IC87114 or 4-PBA alleviated pulmonary inflammation and airway remodelling and reduced ER stress and inflammation-associated intra-ER hyperoxidation, disrupting protein disulfide isomerase (PDI) chaperone activity. IC87114 and 4-PBA also reversed changes in ER membrane fluidity and permeability and the resultant mitochondrial hyperactivation (i.e., Ca2+ accumulation) under hyperoxidation, thereby restoring the physiological state of the ER and mitochondria. These compounds also abolished mitochondria-associated ER membrane (MAM) formation caused by the physical contact between these subcellular organelles.