Background: Group 2 innate lymphoid cells (ILC2s) play important roles in allergic inflammation. However, their roles in the pathophysiology of allergic rhinitis (AR) are poorly understood. Objective: Prevalence of ILC2s in the inferior nasal turbinate (INT) tissues and the activating mechanisms of ILC2s were examined in patients with house dust mite (HDM)-induced AR. Methods: Eighteen patients with HDM-induced AR and 13 control subjects were recruited. Fresh INT tissues and peripheral blood mononuclear cells (PBMCs) were analysed using flow cytometry. Nasal lavage fluids (NLF) were collected at 10 minutes after the nasal provocation test (NPT) with HDM disc, and released mediators were measured by ELISA. Sorted ILC2s were cultured and stimulated with mediators associated with AR. Results: The prevalence of ILC2s was significantly increased in nasal mucosa of patients with HDM-induced AR, and it was positively correlated with the number of infiltrating eosinophils. ILC2s in the INT tissues expressed a prostaglandin D 2 (PGD 2 )receptor, chemoattractant receptor-homologous molecule-expressed TH2 cells (CRTH2) and a cysteinyl leukotriene (cysLTs) receptor, CysLT1. After NPT, the number of eosinophils and concentrations of PGD 2 and cysLTs were significantly increased in the NLF from AR patients. PGD 2 and cysLTs significantly induced IL-5 production from cultured PBMC-derived ILC2s dose-dependently. PGD 2 -induced and cysLTs-induced productions of IL-5 and IL-13 from ILC2s were completely inhibited by ramatroban, a dual CRTH2 and thromboxane receptor antagonist, and montelukast, a CysLT1 antagonist, respectively.Conclusions: PGD 2 -CRTH2 and cysLTs-CysLT1 axes may activate tissue-resident ILC2s to produce Th2 cytokines, IL-5 and IL-13, leading to the development of allergic inflammation in AR.

Cystatin A and SPINK5 play an important role in protecting the airway epithelium from exogenous proteases. The preservation of EPIs may have a therapeutic benefit in intractable airway inflammation, such as eosinophilic CRS.

The epithelial cell-derived cytokines, thymic stromal lymphopoietin (TSLP), interleukin (IL)-25, and IL-33 induce T helper 2 type immune responses. In the present study, we investigate the role of these cytokines in the pathophysiology of eosinophilic chronic rhinosinusitis (ECRS). Nasal tissue specimens from chronic rhinosinusitis patients were assayed for the expression of TSLP, IL-25, IL-33, protease-activated receptor (PAR)-2, and P2Y2 receptor (P2Y2R). Cytokine production in cultured nasal epithelial cells (PNECs) was also examined. The mRNA levels of TSLP and IL-25 and the concentrations of IL-25 and IL-33 increased in PNECs from ECRS patients. Immunohistological staining demonstrated that TSLP, IL-25, and IL-33 were localized in the epithelial cells of nasal polyps, and that their expression was increased in ECRS. The mRNA levels of TSLP and IL-25 correlated with the clinical severity of ECRS, as indicated by the computed tomography score. The TSLP mRNA levels and IL-33 protein concentration correlated with the number of eosinophils in the nasal polyps of patients with ECRS. Airborne allergen-induced cytokine production increased in PNECs of these patients. Expression levels of the PAR-2 and P2Y2R increased in cultured PNECs and nasal polyps from patients with ECRS. The results indicate that increased induction and expression of TSLP, IL-25, and IL-33 from nasal epithelial cells contribute to the pathophysiology of ECRS.

NPFs play important roles in the pathophysiology of CRSwNP such as in nasal polyp formation and inflammatory cell infiltration by releasing cytokines and extracellular matrix proteins. Activated coagulation factors, thrombin and FXa, stimulate the release of these cytokines and fibronectin from NPFs via PARs.

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