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Role of interleukin-23 in the development of nonallergic eosinophilic inflammation in a murine model of asthma.

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??g/mouse) plus polyI:C (0.01??g/mouse) or DEPs (10??g/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-1?; 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.

SUBMITTER: Lee HS

PROVIDER: S-EPMC7000690 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Role of interleukin-23 in the development of nonallergic eosinophilic inflammation in a murine model of asthma.

Lee Hyun Seung HS Park Da-Eun DE Lee Ji-Won JW Sohn Kyung Hee KH Cho Sang-Heon SH Park Heung-Woo HW

Experimental & molecular medicine 20200120 1

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 devel ...[more]

PMID: 31956268

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Project description:Asthma is characterized by episodic, reversible airflow obstruction associated with variable levels of inflammation. Over the past several decades, there has been an increasing appreciation that the clinical presentation of asthma comprises a diverse set of underlying pathologies. Rather than being viewed as a single disease entity, asthma is now thought of as a clinical syndrome with the involvement of multiple pathological mechanisms. While it is appreciated that eosinophilia is present in only a subset of patients, it remains a key feature of asthma and other eosinophilic disorders such as atopic dermatitis, eosinophilic esophagitis, and chronic rhinosinusitis with nasal polyps. Eosinophils are bone marrow-derived leukocytes present in low numbers in health; however, during disease the type 2 cytokines [interleukins (IL)-4, -5, and -13] can induce rapid eosinophilopoiesis, prolonged eosinophil survival, and trafficking to the site of injury. In diseases such as allergic asthma there is an aberrant inflammatory response leading to eosinophilia, tissue damage, and airway pathology. IL-13 is a pleiotropic type 2 cytokine that has been shown to be integral in the pathogenesis of asthma and other eosinophilic disorders. IL-13 levels are elevated in animal models of eosinophilic inflammation and in the blood and tissue of patients diagnosed with eosinophilic disorders. IL-13 signaling elicits many pathogenic mechanisms including the promotion of eosinophil survival, activation, and trafficking. Data from preclinical models and clinical trials of IL-13 inhibitors in patients have revealed mechanistic insights into the role of this cytokine in driving eosinophilia. Promising results from clinical trials further support a key mechanistic role of IL-13 in asthma and other eosinophilic disorders. Here, we provide a perspective on the role of IL-13 in asthma and other eosinophilic disorders and describe ongoing clinical trials targeting this pathway in patients with significant unmet medical needs.

Project description:Allergic asthma is characterized by airway eosinophilia, increased mucin production and allergen-specific IgE. Fc gamma receptor IIb (FcgammaRIIb), an inhibitory IgG receptor, has recently emerged as a negative regulator of allergic diseases like anaphylaxis and allergic rhinitis. However, no studies to date have evaluated its role in allergic asthma. Our main objective was to study the role of FcgammaRIIb in allergic lung inflammation. We used a murine model of allergic airway inflammation. Inflammation was quantified by BAL inflammatory cells and airway mucin production. FcgammaRIIb expression was measured by qPCR and flow cytometry and the cytokines were quantified by ELISA. Compared to wild type animals, FcgammaRIIb deficient mice mount a vigorous allergic lung inflammation characterized by increased bronchoalveolar lavage fluid cellularity, eosinophilia and mucin content upon ragweed extract (RWE) challenge. RWE challenge in sensitized mice upregulated FcgammaRIIb in the lungs. Disruption of IFN-gamma gene abrogated this upregulation. Treatment of naïve mice with the Th1-inducing agent CpG DNA increased FcgammaRIIb expression in the lungs. Furthermore, treatment of sensitized mice with CpG DNA prior to RWE challenge induced greater upregulation of FcgammaRIIb than RWE challenge alone. These observations indicated that RWE challenge upregulated FcgammaRIIb in the lungs by IFN-gamma- and Th1-dependent mechanisms. RWE challenge upregulated FcgammaRIIb on pulmonary CD14+/MHC II+ mononuclear cells and CD11c+ cells. FcgammaRIIb deficient mice also exhibited an exaggerated RWE-specific IgE response upon sensitization when compared to wild type mice. We propose that FcgammaRIIb physiologically regulates allergic airway inflammation by two mechanisms: 1) allergen challenge mediates upregulation of FcgammaRIIb on pulmonary CD14+/MHC II+ mononuclear cells and CD11c+ cells by an IFN-gamma dependent mechanism; and 2) by attenuating the allergen specific IgE response during sensitization. Thus, stimulating FcgammaRIIb may be a therapeutic strategy in allergic airway disorders.

Dataset Information

Role of interleukin-23 in the development of nonallergic eosinophilic inflammation in a murine model of asthma.

Publications

Role of interleukin-23 in the development of nonallergic eosinophilic inflammation in a murine model of asthma.

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