PI3Kδ contributes to ER stress-associated asthma through ER-redox disturbances: the involvement of the RIDD–RIG-I–NF-κB axis

Abstract

Hyperactivation of phosphoinositol 3-kinase (PI3K) has been suggested to be a potential mechanism for endoplasmic reticulum (ER) stress-enhanced airway hyperresponsiveness, and PI3K inhibitors have been examined as asthma therapeutics. However, the regulatory mechanism linking PI3K to ER stress and related pathological signals in asthma have not been defined. To elucidate these pathogenic pathways, we investigated the influence of a selective PI3Kδ inhibitor, IC87114, on airway inflammation in an ovalbumin/lipopolysaccharide (OVA/LPS)-induced asthma model. In OVA/LPS-induced asthmatic mice, the activity of PI3K, downstream phosphorylation of AKT and activation of nuclear factor-κB (NF-κB) were all significantly elevated; these effects were reversed by IC87114. IC87114 treatment also reduced the OVA/LPS-induced ER stress response by enhancing the intra-ER oxidative folding status through suppression of protein disulfide isomerase activity, ER-associated reactive oxygen species (ROS) accumulation and NOX4 activity. Furthermore, inositol-requiring enzyme-1α (IRE1α)-dependent degradation (RIDD) of IRE1α was reduced by IC87114, resulting in a decreased release of proinflammatory cytokines from bronchial epithelial cells. These results suggest that PI3Kδ may induce severe airway inflammation and hyperresponsiveness by activating NF-κB signaling through ER-associated ROS and RIDD–RIG-I activation. The PI3Kδ inhibitor IC87114 is a potential therapeutic agent against neutrophil-dominant asthma.

Inhibition of PI3Kδ Enhances Poly I:C-Induced Antiviral Responses and Inhibits Replication of Human Metapneumovirus in Murine Lungs and Human Bronchial Epithelial Cells

“…In our study, the selective PI3Kδ inhibitor IC87114 attenuated poly I:C-induced inflammatory responses in vivo and in vitro. Other investigators also have showed that IC87114 decreased neutrophilic inflammation in BALF to almost control level (51)(52)(53). These anti-inflammatory effects of IC87114 might contribute to prevention of asthma and COPD exacerbation.…”

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

“…Previous studies have suggested that PI3K‐δ and ER stress are involved in airway inflammation and remodelling (Kim et al, ). To confirm the pathological role of PI3K‐δ and ER stress, we examined the effects of the PI3K‐δ inhibitor IC87114 and the chemical chaperone 4‐PBA that regulates ER stress in an A. fumigatus ‐induced mouse model of airway inflammation.…”

“…Previous studies have suggested that PI3K-δ and ER stress are involved in airway inflammation and remodelling (Kim et al, 2018).…”

Significance of Immune-related Genes in the Diagnosis and Subtype Classification of Childhood Asthma

“…DExD/H-Box Helicase 58 (DDX58), also known as reticonic acid induced gene I (RIG-I), activates and regulates the expression of various in ammatory factors, thereby initiating innate and speci c immune responses 20 . Many studies have shown that RIG-I plays an important role in the in ammatory response of asthma induced by viruses [21][22][23] . Human leukocyte antigen (HLA) is a gene complex closely related to human immune function.…”