Evidence for the induction of Th2 inflammation by group 2 innate lymphoid cells in response to prostaglandin D₂ and cysteinyl leukotrienes in allergic rhinitis

Abstract

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.

The Biology of Prostaglandins and Their Role as a Target for Allergic Airway Disease Therapy

“…The relationship between ILC2 cell function and PGs in allergic disease was first reported in a study showing that PGD 2 released from mast cells induced IL-13 production by ILC2 cells, via DP1 or DP2 receptors ( Figure 4) [79]. ILC2 cells obtained from the peripheral blood of patients with allergic rhinitis induced IL-5 production after stimulation by PGD 2 [80]. Furthermore, activation of DP2 receptor on human ILC2 cells induced their migration, production of type 2 cytokines, and increased expression of receptors for IL-33 and IL-25 [81].…”

Role of IL‐25, IL‐33, and TSLP in triggering united airway diseases toward type 2 inflammation

“…In the murine model, IL‐13 produced by ILC2s caused pulmonary fibrosis under long‐term IL‐25 stimulations. In the human airway context, strong ILC2 effects in response to IL‐25 were observed in the nasal polyps of patients with CRSwNP 43,45 . Increased ILC2 frequencies and activities in response to IL‐25 are inhibited by glucocorticoid treatments via MEK/JAK‐STAT signal pathways in patients with asthma 44 .…”

Recent developments and highlights in allergic rhinitis

“…Group 2 innate lymphoid cells (ILC2s) appear to be critical for allergic diseases in innate immune responses . Tissue‐resident ILC2s produce the Th2 cytokines IL‐5 and IL‐13, which are activated by prostaglandin D2 (PGD2)—chemoattractant receptor homologous molecule expressed TH2 (CRTH2) cells and cysteinyl leukotriene (cysLTs)—cysLTs receptor (CysLT1) axes . A murine study showed that IL‐33 mediates the production of IL‐5 mostly through innate activation of ILC2s, which promotes acute reactive eosinophilopoiesis in the bone marrow following exposure to airborne allergens .…”

“…54,55 Tissue-resident ILC2s produce the Th2 cytokines IL-5 and IL-13, which are activated by prostaglandin D2 (PGD2)-chemoattractant receptor homologous molecule expressed TH2 (CRTH2) cells and cysteinyl leukotriene (cysLTs)-cysLTs receptor (CysLT1) axes. 56 A murine study showed that IL-33 mediates the production of IL-5 mostly through innate activation of ILC2s, which promotes acute reactive eosinophilopoiesis in the bone marrow following exposure to airborne allergens. 57 Decreased number of ILC2s are observed in peripheral blood after nasal allergen challenge (NAC) and are positively correlated with AR symptoms in birch allergic objects irritated outside of the local birch pollen season.…”