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

Hwa‐Young Lee,Yong‐Chul Lee,Han‐Jung Chae,Hyung‐Ryong Kim,Geum‐Hwa Lee

doi:10.1111/bph.14917

Abstract

Background and PurposePhosphatidylinositol 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 ApproachA 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 ResultsTreatment 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 ImplicationsPI3K‐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.

Highlights

Fungi are increasingly recognised as the main cause of allergic asthma, one of the most common respiratory diseases that can lead to chronic airway inflammation, reversible airway obstruction, increased mucus production, and non-specific airway hyper-responsiveness (AHR; Leong & Huston, 2001)
In mice exposed to A. fumigatus and exhibiting an endoplasmic reticulum (ER) stress response (Figure 2a), we examined whether A. fumigatus-induced allergic lung inflammation alters ER membrane fluidity, which could lead to the disruption of calcium homeostasis and increase in ER stress
The results of this study demonstrate that inhibiting phosphoinositide 3-kinase (PI3K)-δ or ER stress can mitigate airway inflammation and remodelling in an A. fumigatus-induced mouse model of severe asthma characterised by ER stress, changes in ER membrane fluidity and permeability, close contact between the ER and mitochondria, and amplified Ca2+ and ROS-induced signalling

Summary

| INTRODUCTION

Fungi are increasingly recognised as the main cause of allergic asthma, one of the most common respiratory diseases that can lead to chronic airway inflammation, reversible airway obstruction, increased mucus production, and non-specific airway hyper-responsiveness (AHR; Leong & Huston, 2001). To maintain its functional integrity, the ER must constantly balance the capacity of its protein chaperones with the load of newly synthesised unfolded proteins in the cell and disrupting this balance leads to the accumulation of unfolded or misfolded proteins in the ER (Hotamisligil, 2010) This process, known as ER stress, is associated with changes to the fluidity and permeability of the ER membrane (Kaplan, Racay, Lehotsky, & Mezesova, 1995; Pamplona, 2008) that result in the propagation of signals to nearby mitochondria (Malhotra & Kaufman, 2011; Marchi, Patergnani, & Pinton, 2014). What is the clinical significance PI3K-δ and ER stress, along with ER–mitochondria interactions, underlie the development of refractory asthma

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Findings

| DISCUSSION