Airway epithelial phosphoinositide 3-kinase-δ contributes to the modulation of fungi-induced innate immune response

Abstract

BackgroundRespiratory fungal exposure is known to be associated with severe allergic lung inflammation. Airway epithelium is an essential controller of allergic inflammation. An innate immune recognition receptor, nucleotide-binding domain, leucine-rich-containing family, pyrin-domain-containing-3 (NLRP3) inflammasome, and phosphoinositide 3 kinase (PI3K)-δ in airway epithelium are involved in various inflammatory processes.ObjectivesWe investigated the role of NLRP3 inflammasome in fungi-induced allergic lung inflammation and examined the regulatory mechanism of NLRP3 inflammasome, focusing on PI3K-δ in airway epithelium.MethodsWe used two in vivo models induced by exposure to Aspergillus fumigatus (Af) and Alternaria alternata (Aa), as well as an Af-exposed in vitro system. We also checked NLRP3 expression in lung tissues from patients with allergic bronchopulmonary aspergillosis (ABPA).ResultsAssembly/activation of NLRP3 inflammasome was increased in the lung of Af-exposed mice. Elevation of NLRP3 inflammasome assembly/activation was observed in Af-stimulated murine and human epithelial cells. Similarly, pulmonary expression of NLRP3 in patients with ABPA was increased. Importantly, neutralisation of NLRP3 inflammasome derived IL-1β alleviated pathophysiological features of Af-induced allergic inflammation. Furthermore, PI3K-δ blockade improved Af-induced allergic inflammation through modulation of NLRP3 inflammasome, especially in epithelial cells. This modulatory role of PI3K-δ was mediated through the regulation of mitochondrial reactive oxygen species (mtROS) generation. NLRP3 inflammasome was also implicated in Aa-induced eosinophilic allergic inflammation, which was improved by PI3K-δ blockade.ConclusionThese findings demonstrate that fungi-induced assembly/activation of NLRP3 inflammasome in airway epithelium may be modulated by PI3K-δ, which is mediated partly through the regulation of mtROS generation. Inhibition of PI3K-δ may have potential for treating fungi-induced severe allergic lung inflammation.

Phosphoinositide 3-kinase-delta could be a biomarker for eosinophilic nasal polyps

“…PI3K-δ has been reported to play an important role in the adaptive immune response involving T- and B-cells 7 , 32 , influencing adaptive T H 2-mediated eosinophilic inflammation. Furthermore, we have reported the crucial modulatory roles of PI3K-δ in the innate immune response at the airway epithelium partly via regulation of epithelial generation of mitochondrial ROS 11 , 12 , which are known to be essential for T H 2 cell-associated eosinophilic inflammation in airways 33 . More recently, reduction of chemokines involved in allergen-induced recruitment of T H 2 lymphocytes (namely, CCL17 and CCL22) by a potent small molecular inhibitor of PI3K-δ has been demonstrated in a phase I clinical study in patients with allergic rhinitis 34 .…”

“…PI3K-δ is also likely to play key roles in generating proper effector functions of eosinophils involving the release of diverse eosinophil-derived mediators ( e.g . granular proteins, lipid mediators, cytokines/chemokines, enzymes, growth factors, and oxidative products) partly through innate receptor-mediated generation of reactive oxygen species (ROS) and pro-inflammatory cytokines 11 , 12 . Several indirect modulatory effects of PI3K-δ on eosinophilic inflammation also seem to exist.…”

“…Immunologic roles of PI3K-δ involve T- and B-cell activation 7 , mast cell degranulation 8 , and the recruitment of eosinophils and neutrophils into inflamed tissue 9 , 10 . In particular, modulation of this signaling pathway has been shown to be effective for ameliorating T H 2-associated eosinophil-dominant lung inflammation including corticosteroid-resistant severe forms of the disease 11 – 13 .…”

Bronchial Epithelial Cells on the Front Line to Fight Lung Infection-Causing Aspergillus fumigatus

“…The SYK-CARD9 pathway also activates the NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) inflammasome, which results in the proteolytic activation of the pro-inflammatory cytokines IL-1β and IL-18 by caspase 1. The role of A. fumigatus antigens in this activation cascade has been demonstrated by Jeong et al They showed that sensitized mice intratracheally challenged with A. fumigatus crude antigens displayed an increased in immunofluorescence intensities of NLRP3 and caspase-1 in lung tissue, particularly in epithelial cell layers, leading to an increase in IL1-β concentration in the lung tissue (53). Similar results were obtained by using an in vitro model utilizing primary human BECs stimulated with the same A. fumigatus antigens (53).…”

Aspergillus fumigatus change Gasdermin-D-dependent pyrolysis of the lung through regulating TRL2-dependent Regulatory T cells differentiation

“…The release of IL-1β in monocytes and the increased spread of pro-IL-1β is stimulated by hyphae while A. fumigatus triggers the release of NLRP3 in ammasomes [(Said-Sadier et al 2010)]. Studies showed that the expression of NLRP3 was increased in lung tissue from patients with allergic bronchopulmonary aspergillosis (ABPA)[ (Jeong et al 2018)]. For the in ammasome to induce the secretion of IL-1β the steps involved include proin ammatory stimuli triggering TLR to mediate signals, cytokines to be induced to produce proform and in ammasomes to be activated to ensure mature processing of cytokines [(Schroder and Tschopp 2010)].…”