An Interleukin-33-Mast Cell-Interleukin-2 Axis Suppresses Papain-Induced Allergic Inflammation by Promoting Regulatory T Cell Numbers

Abstract

SUMMARY House dust mite-derived proteases contribute to allergic disorders in part by disrupting epithelial barrier function. Interleukin-33 (IL-33), produced by lung cells after exposure to protease allergens, can induce innate-type airway eosinophilia by activating natural helper (NH) cells, a member of group 2 innate lymphoid cells (ILC2), to secrete Th2 type-cytokines. Because IL-33 also can induce mast cells (MCs) to secrete Th2 type-cytokines, MCs are thought to cooperate with NH cells in enhancing protease or IL-33-mediated innate-type airway eosinophilia. However, we found that MC-deficient KitW-sh/W-sh mice exhibited exacerbated protease-induced lung inflammation associated with reduced numbers of regulatory T (Treg) cells. Moreover, IL-2 produced by IL-33-stimulated MCs promoted expansion of numbers of Treg cells, thereby suppressing development of papain- or IL-33-induced airway eosinophilia. We have thus identified a unique anti-inflammatory pathway that can limit induction of innate-type allergic airway inflammation mediated by NH cells.

‘Repair’ Treg Cells in Tissue Injury

“…CD73-dependent adenosine generation in Tregs also promoted acute lung injury resolution [32]. Tregs limited injury by decreasing allergic airway inflammation and epithelial barrier disruption in house dust mite-derived protease induced-allergic disorders [33]. In addition, Tregs participate in the maintenance of intestinal homeostasis following damage or inflammation or infection [34-36], which has been well reviewed [37].…”

Type 2 Cytokine Responses: Regulating Immunity to Helminth Parasites and Allergic Inflammation

“…The many functions of ILC2s in the context of models of allergic disease suggest that ILC2 populations might represent a fruitful therapeutic target. It is also possible that negative regulators of ILC2 responses such as type 1(79) and type 2 interferons(80), IL-27(81, 82), KLRG1 signaling by E-cadherin(66), lipoxin A4(83), and T regulatory cells(84, 85) could also be manipulated to reduce ILC2 activation in the context of allergic inflammation.…”

The Skin as a Route of Allergen Exposure: Part I. Immune Components and Mechanisms

“…Supporting the critical role of IL-33, anaphylaxis was blocked by treating mice with an IL-33 receptor antagonist prior to oral challenge and could not be restored in mice lacking IL-33 receptor [54]. Using bone marrow-derived mast cells, previous groups showed that IL-33-stimulated mast cell signaling promotes expansion of T regulatory (Treg) cells in an IL-2-dependent fashion [55]. Given these findings came from in vitro work, the IL-33/Th2 pathway may be confined to tissue-resident mast cells.…”