Synergistic relationship between TSLP and IL‐33/ST2 signaling pathways in allergic rhinitis and the effects of hypoxia

Abstract

Background:The World Health Organization (WHO) has noted that allergic diseases are a major health problem of the 21st century. Allergic rhinitis (AR) is a type I allergic disease characterized by nasal mucosa and immune system abnormalities. AR is mediated by various inflammatory cells and is mainly characterized by altered secretion of cytokines. Thymic stromal lymphopoietin (TSLP) and the interleukin-33/stimulation-expressed gene 2 (IL-33/ST2) signaling pathway are cytokines that play pivotal roles in many inflammatory responses and allergic reactions. There have been reports of interactions between the 2 pathways in many diseases. Hypoxia is a common pathologic manifestation of AR. The aim of this study was to explore the relationship and expressions and biologic functions of TSLP and IL-33/ST2 in AR, and also to determine the effects of hypoxia on these cytokines. Methods:The rat nasal mucosal epithelium was obtained from Wistar rats. Cells were cultured in groups under hypoxia and normoxia conditions. Identification of rat nasal epithelial cell (RNEpC) and protein expressions was done by immunohistochemistry and immunofluorescence methods. Cell proliferation and migration were examined using the cell counting kit-8 (CCK-8) and Transwell kit. Detection of apoptosis was tested using a fluorescence apoptosis kit. Enzyme-linked immunoassay (ELISA) and Western blot analysis ELISA were used to measure cell secretion and protein expressions. For these experiments, TSLP was knocked down by lentivirus transfection and IL-33 blocked with its antagonist.Results: TSLP, IL-33, and ST2 expressions were significantly higher in nasal mucosa epithelial cells from AR rats than in those from control rats. Hypoxia further promoted their expression. Increased TSLP and IL-33/ST2 promoted cell proliferation, inhibited cell apoptosis, and enhanced cell migration. In addition, the downregulation of TSLP expression effectively a enuated expression of the IL-33/ST2 axis and, through use of IL-33 antagonists, could also reduce TSLP expression, a synergistic effect more obvious under hypoxia. Conclusion:Our data indicate that TSLP and IL-33/ST2 signaling pathways interact with each other in the pathogenesis and pathologic development of AR. TSLP inhibition is a key factor in AR treatment. Inhibiting hypoxia-induced pathologic processes could represent a therapeutic effect by inhibiting IL-33/ST2 expression via downregulating TSLP. C 2020 ARS-AAOA, LLC.

Serum Soluble ST2 Correlated with Symptom Severity and Clinical Response of Sublingual Immunotherapy for House Dust Mite-Induced Allergic Rhinitis Patients

“…Our observations were in line with previous results in other allergic diseases such as food allergy, asthma, and atopic dermatitis [ 20 , 30 , 35 ]. ST2 was a key mediator regulating the functions of immune cells and was involved in the antigen-presenting process and promoting the immune response [ 15 , 32 ]. When patients were exposed to an allergic environment, the allergens will stimulate the endothelial cells and epithelial cells and predominantly promote the secretion of IL-33, the increased levels of IL-33 will upregulate the expression of ST2 especially in the dendritic cells, the activated dendritic cells will enhance CD4+ T differentiation to Th2 cells and induce the production of Th2-type cytokines (IL-4, IL-5, and IL-13), and the high concentrations of these cytokines will cause the activation of B cells and secretion of IgE and enhance the mast cell degranulation and histamine release, resulting in exacerbation of allergic symptoms in AR patients [ 36 – 38 ].…”

<i>Chamaecyparis obtusa</i> Essential Oil Inhibits House Dust Mite Induced Nasal Epithelial Cell Activation and Immune Responses

“…Type-2-cell mediated immune stimuli induce the production of IL-25, IL-33, and TSLP that activate dendritic cells to promote the Th2 immune response through the activation of type 2 innate lymphoid cells ILC2s , basophils, eosinophils, and mast cells 2,24 . IL-25, IL-33, and TSLP also promote the differentiation of ILC2s.…”

Influence of interleukin-33 gene expression on clinical and morphological characteristics of the nasal mucosa in allergic rhinitis

“…В работе R. Huang [41] было зарегистрировано снижение содержания ИЛ-33 и TSLP, что провоцировало апоптоз в культуре клеток эпителия, но уровень секреции ИЛ-33 был выше в культуре клеток назального эпителия, выращенной в условия гипоксии, а также в группе пациентов с АР в сопоставлении с группой сравнения. При анализе взаимодействия сигнальных путей ИЛ-33 и TSLP показано, что при подавлении экспрессии TSLP значительно снижается экспрессия ИЛ-33 и ST2.…”