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

Abstract

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., 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. 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.

Beyond Proteostasis: Lipid Metabolism as a New Player in ER Homeostasis

“…4-PBA reduces Ire1p levels instead of unfolded protein load, providing an alternative interpretation of the above results [ 104 ]. Furthermore, 4-PBA and TUDCA have functions beyond protein refolding, such as reducing lipid accumulation [ 105 ] and membrane cholesterol levels [ 106 ], as well as restoring ER lipid fluidity and calcium permeability [ 107 ]. Therefore, interpreting results from experiments with chemical chaperones is challenging.…”

NOD1 and NOD2 Activation by Diverse Stimuli: a Possible Role for Sensing Pathogen-Induced Endoplasmic Reticulum Stress

“…2), which required mitochondrial ROS production (152,153). Interestingly, ER stress inhibition using 4-phenylbutyric acid (4-PBA) during A. fumigatus infection in an asthma mouse model reduced pulmonary inflammation, ROS generation, ER calcium depletion, and NLRP3 inflammasome activation (153). Thus, ER stress mediated by A. fumigatus infection leads to damaging inflammatory responses.…”

CpG Oligodeoxynucleotides Attenuate OVA-Induced Allergic Airway Inflammation via Suppressing JNK-Mediated Endoplasmic Reticulum Stress

“… 40 Blocking ER stress by inhibitor 4PBA could alleviate allergic airway inflammation. 41 Under normal circumstances, the three transmembrane proteins of ATF6, IRE1 and PERK on the ER membrane act as receptors of the ER and tightly bind to GRP78 to maintain the homeostasis state of ER. 42 Once stressed, misfolded proteins accumulate in the cavity of ER, and GRP78 dissociates from the transmembrane proteins, leading to GRP78, ATF6, IRE1 and PERK activation.…”