Combinatorial IL-17RB, ST2, and TSLPR Signaling in Dendritic Cells of Patients With Allergic Rhinitis.

Rui Zheng,Yang Chen,Xuekun Huang,Jianbo Shi,Yueqi Sun,Qintai Yang,Kai Wang

doi:10.3389/fcell.2020.00207

Abstract

ObjectivesMyeloid dendritic cells (DCs) in patients with allergic rhinitis (AR) express higher levels of IL-17RB, ST2, and TSLPR. However, their functional roles in DCs are much less clear. This study aimed to determine the combined effects of these three receptor signals on the T cell-polarizing function of DCs in AR patients.MethodsMonocyte-derived DCs (mo-DCs) were generated and stimulated with Toll-like receptor (TLR) 1–9 ligands. Der.p1-induced mo-DCs were stimulated with different combinations of IL-25, IL-33, and TSLP to determine phenotypic characteristics and then co-cultured with CD4+ T cells to assess Th2 cytokine production. Expression levels of IL-17RB, ST2, and TSLPR on myeloid DCs (mDCs) from peripheral blood of AR and healthy subjects were detected to confirm the association of these receptors with disease severity.ResultsTLR ligands induced AR-derived mo-DCs to increase IL-17RB, ST2, and TSLPR expression by varying degrees; among these, Der.p1 was the strongest inducer. Der.p1-induced mo-DCs from AR showed increased OX40L expression. IL-25, IL-33, and TSLP (alone or in double combination) significantly increased OX40L expression on Der.p1-induced mo-DCs from AR, thereby increasing the production of IL-4, IL-5, and IL-13 in co-cultured CD4+ T cells; triple combination further enhanced these effects. The percentage of IL-17RB+ST2+TSLPR+ mDCs was increased in AR, higher in moderate to severe phase than in mild phase, and positively correlated with the percentages of IL-4+, IL-5+, and IL-13+ T cells.ConclusionA combination of IL-17RB, ST2, and TSLPR signals amplified the Th2-polarizing function of DCs and was associated with disease severity in AR patients.

Highlights

Allergic rhinitis (AR) is a prevalent disease both in China and Western countries, affecting approximately 10–40% of people worldwide (Salo et al, 2014; Zuberbier et al, 2014; Zhang and Zhang, 2019)
We found that Der.p1 upregulated CD86 expression on mo-Dendritic cells (DCs) derived from both healthy control (HC) and AR subjects (Figures 2A,B)
We determined the effects of IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) on the phenotype of Der.p1-induced Monocyte-derived DCs (mo-DCs) cultured in the presence of IL-25, IL-33, and TSLP, alone or in combination

Summary

Introduction

Allergic rhinitis (AR) is a prevalent disease both in China and Western countries, affecting approximately 10–40% of people worldwide (Salo et al, 2014; Zuberbier et al, 2014; Zhang and Zhang, 2019). AR is an IgE-mediated type 2 inflammatory disorder caused by the interaction of airborne allergens. AR is characterized by inflammatory infiltrates, Mechanism Underlying Allergic Rhinitis predominantly comprising eosinophils, mast cells, basophils, and T cells, which release granule proteins, cytokines, and chemokines to trigger the onset of clinical symptoms such as rhinorrhea, sneezing, nasal itching, and nasal congestion (Bousquet et al, 2008; Cheng et al, 2018; Wise et al, 2018). AR severity is typically classified as either mild (M-AR) or moderate to severe (MS-AR) based on symptom severity according to Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines (Bousquet et al, 2008). The mechanism driving the development of this form remains unclear

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