Abstract
Nonallergic eosinophilic asthma (NAEA) is a clinically distinct subtype of asthma. Thus far, the pathophysiologic mechanisms underlying NAEA have not been fully elucidated. This study aimed to determine the role of IL-23 in the pathogenesis of NAEA. We developed a murine model of NAEA using recombinant IL-23 (rIL-23) plus a nonspecific airway irritant [polyinosinic-polycytidylic acid (polyI:C) or diesel exhaust particles (DEPs)] and investigated whether IL-23 plays an important role in the development of NAEA. Intranasal administration of rIL-23 (0.1 μg/mouse) plus polyI:C (0.01 μg/mouse) or DEPs (10 μg/mouse) without allergen resulted in methacholine bronchial hyperresponsiveness and eosinophilic airway inflammation in mice, which are characteristic features of NAEA. rIL-23 plus a low dose nonspecific airway irritants induced the release of innate cytokines from airway epithelium, including IL-33, thymic stromal lymphopoietin and IL-1β; these factors activated types 2 and 3 innate lymphoid cells (ILC2s and ILC3s). ILC2s and ILC3s, but not CD4+ T cells (i.e., adaptive immune cells), were important in the development of NAEA. In addition, we observed that IL-23 receptor expressions increased in airway epithelial cells, which suggests the existence of a positive autocrine loop in our murine model of NAEA. To our knowledge, this is the first report in which administration of rIL-23 plus a nonspecific airway irritant (polyI:C or DEPs) without allergen resulted in features of NAEA in mice similar to those found in humans. IL-23 may constitute a therapeutic target for NAEA in humans.
Highlights
The classical paradigm of asthma pathogenesis involves an allergic response: allergen-specific T helper type 2 (Th2) cells produce cytokines that regulate the allergenspecific synthesis of immunoglobulin E (IgE) and the recruitment of eosinophils[1]
A significant increase in the number of eosinophils was observed only in mice treated with 1 μg/mouse recombinant IL-23 (rIL-23)
The number of IL-13 or IL-5producing ILC2s (CD45+Lin−inducible T cell costimulator (ICOS)+) and IL-17producing ILC3s (CD45+Lin−CD25+) significantly increased in mice treated with 1 μg/mouse rIL-23 (Fig. 1d, e, S5a–c)
Summary
The classical paradigm of asthma pathogenesis involves an allergic response: allergen-specific T helper type 2 (Th2) cells produce cytokines that regulate the allergenspecific synthesis of immunoglobulin E (IgE) and the recruitment of eosinophils[1]. In practice, some patients with asthma have negative skin prick test results when exposed to a panel of common allergens or have no allergen-specific IgE. This nonallergic asthma occurs in 10–33% of patients with asthma, and has a later onset than allergic asthma[2]. Recent advances in the immunologic understanding of asthma pathogenesis have revealed that interactions between innate and adaptive immunity produce heterogenetic features, including nonallergic eosinophilic asthma (NAEA), a distinct subtype of asthma[7]
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