PI3K-Delta Signaling Pathway Is Required for the Assembly of NLRP3 Inflammasome in Bronchial Epithelium of HDM-Induced Allergic Asthma

Phosphoinositide 3-kinase (PI3K)-δ-dependent Akt activation is associated with the pathogenesis of severe respiratory diseases partly through the induction of steroid resistance. However, the role of PI3K-δ isoform is still controversy in allergic inflammation. Moreover, many studies to define the role of PI3K-δ in inflammatory conditions have focused its action in immune/inflammatory cells. With trend a major pathobiological mechanism for asthma including severe form has shifted toward defects in epithelial innate immune responses to injury from typical Th2-biased adaptive immune responses, epithelial cells has resurfaced as one of immune effector cells. This study aimed to the role of PI3K-δ isoform in the house dust mite (HDM)-induced allergic responses, focusing on NLRP3 inflammasome activation. We used a murine model of HDM-induced asthma and also performed in vitro experiments using primary cultured murine tracheal epithelial cells and human bronchial epithelial cells. We found that PI3K-δ inhibition decreased HDM-induced typical allergic asthmatic features including PI3K-δ mRNA expression and the activation of NLRP3 inflammasome in lung and primary cultured tracheal epithelial cells from mice. Interestingly, in LPS-stimulated airway epithelial cells, significant increased expression of PI3K-δ isoform was observed and the increases were markedly suppressed by chemical inhibition for TLR4 or PI3K-δ. This study indicates that HDM allergens activate NLRP3 inflammasome in the lung, specifically in airway epithelial cells through TLR4-PI3K-d axis activation, highlighting the therapeutic potential of PI3K-δ targeting agents as well as the role of bronchial epithelial cells as an immune effector in allergic airway inflammation.