PI3K-δ controls endoplasmic reticulum membrane fluidity and permeability in fungus-induced allergic inflammation.

PI3K-δ controls endoplasmic reticulum membrane fluidity and permeability in fungus-induced allergic inflammation.

Br J Pharmacol. 2019 Nov 12;:

Authors: Lee HY, Lee GH, Kim HR, Lee YC, Chae HJ

Abstract
BACKGROUND AND PURPOSE: Phosphoinositol 3-kinase (PI3K)-especially PI3K-δ-and endoplasmic reticulum (ER) stress play important roles in refractory asthma induced by the fungus Aspergillus fumigatus (Af) through mechanisms that are not well understood. This was investigated in the present study using BEAS-2B human bronchial epithelial cells and a mouse model of Af-induced allergic lung inflammation.
EXPERIMENTAL APPROACH: A selective PI3K-δ inhibitor IC87114 and an ER-folding chaperone chemical 4-PBA were applied to the Aspergillus fumigatus (Af)-induced asthma mouse model. The therapeutic potential of IC87114 and 4-PBA were addressed by determining its activity in relevant primate cell, tissue, and disease models.
KEY RESULTS: Our results show that treatment with the PI3K-δ inhibitor IC87114 or ER stress inhibitor 4-phenylbutyric acid (4-PBA) alleviated pulmonary inflammation and airway remodeling and reduced ER stress and inflammation-associated intra-ER hyperoxydation, 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; they also abolished mitochondria-associated ER membrane (MAM) formation caused by the physical contact between these subcellular organelles.
CONCLUSIONS AND IMPLICATIONS: These results indicate that PI3K-δ and ER stress mediate Af-induced allergic lung inflammation by altering the ER redox state, PDI chaperone function, and ER membrane fluidity and permeability, and by amplifying ER signaling 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.

PMID: 31713846 [PubMed – as supplied by publisher]

Source: Industry