Persistence of asthma requires multiple feedback circuits involving type 2 innate lymphoid cells and IL-33.

Autor: Christianson CA; Division of Allergy and Immunology, National Jewish Health, Denver, Colo., Goplen NP; Division of Allergy and Immunology, National Jewish Health, Denver, Colo., Zafar I; Division of Allergy and Immunology, National Jewish Health, Denver, Colo., Irvin C; Division of Allergy and Immunology, National Jewish Health, Denver, Colo., Good JT Jr; Division of Pulmonary Medicine, Department of Medicine, National Jewish Health, Denver, Colo., Rollins DR; Division of Pulmonary Medicine, Department of Medicine, National Jewish Health, Denver, Colo., Gorentla B; Division of Allergy and Immunology, National Jewish Health, Denver, Colo., Liu W; Division of Allergy and Immunology, National Jewish Health, Denver, Colo., Gorska MM; Division of Allergy and Immunology, National Jewish Health, Denver, Colo; University of Colorado Denver, Denver, Colo., Chu H; Division of Pulmonary Medicine, Department of Medicine, National Jewish Health, Denver, Colo; University of Colorado Denver, Denver, Colo., Martin RJ; Division of Pulmonary Medicine, Department of Medicine, National Jewish Health, Denver, Colo; University of Colorado Denver, Denver, Colo., Alam R; Division of Allergy and Immunology, National Jewish Health, Denver, Colo; University of Colorado Denver, Denver, Colo. Electronic address: AlamR@njhealth.org.
Jazyk: angličtina
Zdroj: The Journal of allergy and clinical immunology [J Allergy Clin Immunol] 2015 Jul; Vol. 136 (1), pp. 59-68.e14. Date of Electronic Publication: 2015 Jan 21.
DOI: 10.1016/j.jaci.2014.11.037
Abstrakt: Background: Asthma in a mouse model spontaneously resolves after cessation of allergen exposure. We developed a mouse model in which asthma features persisted for 6 months after cessation of allergen exposure.
Objective: We sought to elucidate factors contributing to the persistence of asthma.
Methods: We used a combination of immunologic, genetic, microarray, and pharmacologic approaches to dissect the mechanism of asthma persistence.
Results: Elimination of T cells though antibody-mediated depletion or lethal irradiation and transplantation of recombination-activating gene (Rag1)(-/-) bone marrow in mice with chronic asthma resulted in resolution of airway inflammation but not airway hyperreactivity or remodeling. Elimination of T cells and type 2 innate lymphoid cells (ILC2s) through lethal irradiation and transplantation of Rag2(-/-)γc(-/-) bone marrow or blockade of IL-33 resulted in resolution of airway inflammation and hyperreactivity. Persistence of asthma required multiple interconnected feedback and feed-forward circuits between ILC2s and epithelial cells. Epithelial IL-33 induced ILC2s, a rich source of IL-13. The latter directly induced epithelial IL-33, establishing a positive feedback circuit. IL-33 autoinduced, generating another feedback circuit. IL-13 upregulated IL-33 receptors and facilitated IL-33 autoinduction, thus establishing a feed-forward circuit. Elimination of any component of these circuits resulted in resolution of chronic asthma. In agreement with the foregoing, IL-33 and ILC2 levels were increased in the airways of asthmatic patients. IL-33 levels correlated with disease severity.
Conclusions: We present a critical network of feedback and feed-forward interactions between epithelial cells and ILC2s involved in maintaining chronic asthma. Although T cells contributed to the severity of chronic asthma, they were redundant in maintaining airway hyperreactivity and remodeling.
(Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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