Persistence of asthma requires multiple feedback circuits involving type 2 innate lymphoid cells and IL-33 - 03/07/15
Abstract |
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.
Le texte complet de cet article est disponible en PDF.Key words : Type 2 innate lymphoid cells, IL-33, T cells, feedback circuit, chronic asthma
Abbreviations used : BAL, γc, CRTH2, DRA, ERK, H&E, ILC, ILC2, IL-33R, Rag
Plan
| Supported by National Institutes of Health grants RO1 AI68088, AI091614, RO1 AI102943, U19 AI100275, and PPG HL36577. |
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| Disclosure of potential conflict of interest: This study was funded by the National Institutes of Health. C. A. Christianson's institution has received funding from the National Institutes of Health (NIH); has received compensation for travel and other meeting-related expenses from the American Academy of Allergy, Asthma & Immunology (AAAAI); and is employed by the Ferring Research Institute. J. T. Good, Jr, is employed by National Jewish Health; has received payment for providing expert testimony; has received or has grants pending from MedImmune; has received payment for delivering lectures from AstraZeneca, Merck, and Genentech; and has received payment for the development of educational presentations from QuantaMD. R. J. Martin is employed by National Jewish Health and has received consultancy fees from BI, Theron, and Teva Pharmaceuticals; he and/or his institution have received or have grants pending from MedImmune and the National Heart, Lung, and Blood Institute; and he receives royalties from UpToDate. R. Alam's institution has received funding from the NIH. The rest of the authors declare that they have no relevant conflicts of interest. |
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| Microarray data were submitted to the National Institutes of Health's Gene Expression Omnibus repository. The accession number is GSE54297. |
Vol 136 - N° 1
P. 59 - juillet 2015 Retour au numéro
Article précédent
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