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Phosphatidylinositol 3‐kinase‐δ controls endoplasmic reticulum membrane fluidity and permeability in fungus‐induced allergic inflammation in mice
Author(s) -
Lee HwaYoung,
Lee GeumHwa,
Kim HyungRyong,
Lee YongChul,
Chae HanJung
Publication year - 2020
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.14917
Subject(s) - endoplasmic reticulum , unfolded protein response , microbiology and biotechnology , chemistry , protein disulfide isomerase , inflammation , membrane fluidity , phosphatidylinositol , pi3k/akt/mtor pathway , aspergillus fumigatus , biology , immunology , biochemistry , kinase , signal transduction , membrane
Background and Purpose 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 Results 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., Ca 2+ 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. Conclusion and Implications PI3K‐δ and ER stress mediate A. fumigatus ‐induced allergic lung inflammation by altering the ER redox state, PDI chaperone function, and ER membrane fluidity and permeability and by amplifying ER signalling to mitochondria through MAM formation. Thus, therapeutic strategies that target the PI3K‐δ–ER stress axis could be an effective treatment for allergic asthma caused by fungi.