Divergent Effects of Acute and Prolonged Interleukin 33 Exposure on Mast Cell IgE-Mediated Functions.

Elin Rönnberg,Michel Arock,Mattias Enoksson,Jesper Säfholm,Maria Ekoff,Gunnar Nilsson,Avan Ghaib,Carlos Ceriol

doi:10.3389/fimmu.2019.01361

Abstract

Background: Epithelial cytokines, including IL-33 and Thymic stromal lymphopoietin (TSLP), have attracted interest because of their roles in chronic allergic inflammation-related conditions such as asthma. Mast cells are one of the major targets of IL-33, to which they respond by secreting cytokines. Most studies performed thus far have investigated the acute effects of IL-33 on mast cells. In the current study, we investigated how acute vs. prolonged exposure of mast cells to IL-33 and TSLP affects mediator synthesis and IgE-mediated activation.Methods: Human lung mast cells (HLMCs), cord blood-derived mast cells (CBMCs), and the ROSA mast cell line were used for this study. Receptor expression and the levels of mediators were measured after treatment with IL-33 and/or TSLP.Results: IL-33 induced the release of cytokines. Prolonged exposure to IL-33 increased while TSLP reduced intracellular levels of tryptase. Acute IL-33 treatment strongly potentiated IgE-mediated activation. In contrast, 4 days of exposure to IL-33 decreased IgE-mediated activation, an effect that was accompanied by a reduction in FcεRI expression.Conclusion: We show that IL-33 plays dual roles in mast cells, in which its acute effects include cytokine release and the potentiation of IgE-mediated degranulation, whereas prolonged exposure to IL-33 reduces IgE-mediated activation. We conclude that mast cells act quickly in response to the alarmin IL-33 to initiate an acute inflammatory response, whereas extended exposure to IL-33 during prolonged inflammation reduces IgE-mediated responses. This negative feedback effect suggests the presence of a novel regulatory pathway that modulates IgE-mediated human mast cell responses.

Highlights

Compelling evidence suggests that epithelial cell-derived cytokines, such as thymic stromal lymphopoietin (TSLP), and interleukin (IL) 33 (IL-33), are strongly involved in the initiation and/or perpetuation of allergy and chronic inflammatory lung diseases such as asthma [1,2,3]
Cells that respond to TSLP and IL-33 include T-lymphocytes, type 2 innate lymphoid cells, eosinophils, neutrophils, basophils and mast cells, many of which are often associated with type 2 immune responses, such as allergies [6, 7]
The surface expression level of TSLP-R was higher in ROSA cells than in the primary Cord blood -derived mast cells (CBMCs) and human lung mast cells (HLMCs) (Figure 1A)

Summary

Introduction

Compelling evidence suggests that epithelial cell-derived cytokines, such as thymic stromal lymphopoietin (TSLP), and interleukin (IL) 33 (IL-33), are strongly involved in the initiation and/or perpetuation of allergy and chronic inflammatory lung diseases such as asthma [1,2,3]. Data have accumulated over the years from extensive investigations performed in experimental models, both in vivo and in vitro, as well as from genome wide association studies [4] and clinical trials [5] Both TSLP and IL-33 are released from epithelial cells in response to pathogens, environmental pollutants and allergens, or, in the case of IL-33, as a result of cell damage. Whether mast cells synthesize lipid mediators, such as prostaglandins and leukotrienes, in response to TSLP and IL-33 is less clear and might depend on species differences and/or the type of mast cell [10,11,12, 14,15,16,17] It does not induce mast cell degranulation on its own, IL-33 increases the synthesis and the amount of pre-stored granule mediators [18, 19] and augments IgE-mediated mast cell activation [15, 20, 21], and it can potentially aggravate an allergic reaction. We investigated how acute vs. prolonged exposure of mast cells to IL-33 and TSLP affects mediator synthesis and IgE-mediated activation

Methods

Results

Discussion

Conclusion