Allergic inflammation is initiated by IL-33-dependent crosstalk between mast cells and basophils.

Chia-Lin Hsu,Krishan D. Chhiba,Sergejs Berdnikovs,Shweta Hosakoppal,Rebecca Krier-Burris,Mendy L. Miller,Paul J. Bryce,Hiroyasu Nakano

doi:10.1371/journal.pone.0226701

Abstract

IgE-primed mast cells in peripheral tissues, including the skin, lung, and intestine, are key initiators of allergen-triggered edema and inflammation. Particularly in severe forms of allergy, this inflammation becomes strongly neutrophil dominated, and yet how mast cells coordinate this type of response is unknown. We and others have reported that activated mast cells––a hematopoietic cell type––can produce IL-33, a cytokine known to participate in allergic responses but generally considered as being of epithelial origin and driving Type 2 immune responses (e.g., ILC2 and eosinophil activation). Using models of skin anaphylaxis, our data reveal that mast cell-derived IL-33 also initiates neutrophilic inflammation. We demonstrate a cellular crosstalk mechanism whereby activated mast cells crosstalk to IL-33 receptor–bearing basophils, driving these basophils to adopt a unique response signature rich in neutrophil-associated molecules. We further establish that basophil expression of CXCL1 is necessary for IgE-driven neutrophilic inflammation. Our findings thus unearth a new mechanism by which mast cells initiate local inflammation after antigen triggering and might explain the complex inflammatory phenotypes observed in severe allergic diseases. Moreover, our findings (i) establish a functional link from IL-33 to neutrophilic inflammation that extends IL-33–mediated biology well beyond that of Type 2 immunity, and (ii) demonstrate the functional importance of hematopoietic cell–derived IL-33 in allergic pathogenesis.

Highlights

IgE-associated responses to allergens is a central initiating process in atopic diseases, including asthma, food allergy and urticarial reactions
We previously demonstrated that IL-33 was elevated several hours into the time course of the mast cell–dependent Passive cutaneous anaphylaxis (PCA) model and that ST2 was required for the antigen-driven tissue inflammation (ADTI) response [6]
Significant attention has been paid to the idea that IL-33 is a tissue-derived, constitutively expressed cytokine that resides in the nucleus of structural cells and acts as an alarmin when released after cellular damage [36]

Summary

Introduction

IgE-associated responses to allergens is a central initiating process in atopic diseases, including asthma, food allergy and urticarial reactions. Similar to thymic stromal lymphopoietin (TSLP) and IL-25, IL-33 is understood to drive the initiation of type 2–associated immune responses [7]; IL-33 functions through its receptor, ST2, which is highly expressed on Th2 cells, mast cells, basophils, eosinophils, and type 2 cytokine–producing innate lymphoid cells (ILC2s) This is clinically relevant, as polymorphisms in both IL-33 and ST2 closely associate with asthma in human patients [8]. Studies by our group and others show that DC-derived IL33 is sufficient to promote subsequent Th2 immunity in response to IgG immune complexes [14], and macrophage-derived IL-33 has shown a similar function to promote Th2 immunity during helminth infection [16] In contrast to these innate roles, inducible expression of IL-33 by mast cells activated by antigen-specific IgE represents a role for IL-33 during events associated with adaptive immunity. Our data demonstrate a functional effector role for mast cell–derived IL-33 in which it functions to initiate a molecular and cellular cascade that leads to the neutrophilic inflammation observed after exposure to allergens

Results

Discussion

Experimental procedures