PI3-Kinase Regulates Eosinophil and Neutrophil Degranulation in Patients with Allergic Rhinitis and Allergic Asthma Irrespective of Allergen Challenge Model

Abstract

The PI3K pathway plays a major role in many vital cell processes. Our primary aim was to investigate signalling through PI3K for in vitro degranulation from allergen-primed eosinophils and neutrophils in allergic rhinitis and allergic asthma after seasonal and experimental allergen challenge. Nine patients with allergic rhinitis, eight with allergic asthma and four controls were studied during birch pollen season and after nasal and bronchial allergen challenge. Primed blood eosinophils and neutrophils were stimulated for in vitro degranulation with C3b-coated Sephadex particles, after prior incubation with Wortmannin, a PI3K inhibitor. The released amounts of eosinophil cationic protein (ECP), eosinophil peroxidase (EPO) and myeloperoxidase (MPO) were measured by radioimmunoassay. Wortmannin (10(-6) to 10(-9) M) inhibited ECP, EPO and MPO release in a dose-dependent manner in allergic rhinitis and allergic asthma in all three allergen challenge models. Inhibition of ECP release tended to be lower in the asthmatics in all allergen challenge models, statistically significant compared to the controls during season for 10(-8) M Wortmannin (p=0.01). A clear propensity towards less inhibition in the rhinitic patients was seen after nasal and bronchial challenge compared to seasonal exposure, significant for ECP (10(-8) M Wortmannin; p=0.034 and 0.002, respectively). Signalling through PI3K is clearly involved in ECP, EPO and MPO release in allergic rhinitis and allergic asthma irrespective of allergen challenge model. Allergic asthma demonstrated less inhibition of ECP release via PI3K during pollen season, indicating that other pathways play a greater role in eosinophil degranulation in allergic asthma than allergic rhinitis.

Circulating microRNAs as biomarkers in patients with allergic rhinitis and asthma

“…46,47 The majority of the miRNA groups also target the phosphoinositide 3-kinase-Akt pathway, which is another particularly well-studied signaling cascade in T H 2 inflammation. 48,49 Furthermore, there is emerging evidence in the literature that implicates neurotrophin 50,51 and insulin signaling in patients with allergic lung diseases. 52 Focal adhesion pathways targeted by group 2 and 3 miRNAs in our study are likely involved in changes in airway basement membrane and airway smooth muscle in asthmatic patients.…”

Phosphatidylinositol 3-kinases pathway mediates lung caspase-1 activation and high mobility group box 1 production in a toluene-diisocyanate induced murine asthma model

“…PI3Ks are thought to be involved in a number of pathological states such as cancer, inflammation and allergy. Studies also showed that PI3K pathway plays a crucial role in the pathogenesis of asthma (Kampe et al, 2012;Ro et al, 2013;Takeda et al, 2010). In vitro, PI3K was required for activation of caspase-1, secretion of IL-1b and IL-18, as well as nucleocytoplasmic translocation of HMGB1 (Oh et al, 2009;Tapia-Abellan et al, 2014).…”

NOX2-Derived ROS-Mediated Surface Translocation of BLT1 Is Essential for Exocytosis in Human Eosinophils Induced by LTB₄

“…Upon stimulation by chemotactic factors or chemokines, transmigrated eosinophils arrive in inflamed tissues and are further activated by the proinflammatory microenvironment, which leads to diverse cellular responses, such as adhesion to extracellular matrix proteins, neutrophils or T cells, degranulation and production of cytokines, chemokines or cysteinyl leukotrienes [22,23,24]. Among those responses, degranulation plays a direct role in eliciting eosinophil-mediated tissue inflammatory responses [25]. In particular, degranulation via granule exocytosis resulting from an intracellular granular membrane fusing with a plasma membrane facilitates innate immune responses by releasing cytotoxic granular proteins and preformed chemokines or cytokines, and by delivering reserved chemotactic factor receptors, integrins or adhesive molecules to the cell surface [26,27,28,29].…”