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Lookup NU author(s): Dr Lee Borthwick
This is the authors' accepted manuscript of an article that has been published in its final definitive form by American Association for the Advancement of Science (AAAS), 2016.
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Thymic stromal lymphopoietin (TSLP), interleukin-25 (IL-25), and IL-33 are important initiators of type 2-associated mucosal inflammation and immunity. However, their role in the maintenance of progressive type 2 inflammation and fibrosis is much less clear. Using chronic models of helminth infection and allergic lung inflammation, we show that collective disruption of TSLP, IL-25, and IL-33 signaling suppresses chronic and progressive type 2 cytokine-driven inflammation and fibrosis. In a schistosome lung granuloma model or during chronic Schistosoma mansoni infection in the liver, individual ablation of TSLP, IL-25, or IL-33/ST2 had no impact on the development of IL-4/IL-13-dependent inflammation or fibrosis. However, significant reductions in granuloma-associated eosinophils, hepatic fibrosis, and IL-13-producing type 2 innate lymphoid cells (ILC2s) were observed when signaling of all three mediators was simultaneously disrupted. Combined blockade through monoclonal antibody (mAb) treatment also reduced IL-5 and IL-13 expression during primary and secondary granuloma formation in the lungs. In a model of chronic house dust mite-induced allergic lung inflammation, combined mAb treatment did not decrease established inflammation or fibrosis. TSLP/IL-33 double-knockout mice treated with anti-IL-25 mAb during priming, however, displayed decreased inflammation, mucus production, and lung remodeling in the chronic phase. Together, these studies reveal partially redundant roles for TSLP, IL-25, and IL-33 in the maintenance of type 2 pathology and suggest that in some settings, early combined targeting of these mediators is necessary to ameliorate progressive type 2-driven disease.
Author(s): Vannella KM, Ramalingam TR, Borthwick LA, Barron L, Hart KM, Thompson RW, Kindrachuk KN, Cheever AW, White S, Budelsky AL, Comeau MR, Smith DE, Wynn TA
Publication type: Article
Publication status: Published
Journal: Science Translational Medicine
Year: 2016
Volume: 8
Issue: 337
Print publication date: 04/05/2016
Acceptance date: 30/03/2016
Date deposited: 01/07/2016
ISSN (print): 1946-6234
ISSN (electronic): 1946-6242
Publisher: American Association for the Advancement of Science (AAAS)
URL: http://dx.doi.org/10.1126/scitranslmed.aaf1938
DOI: 10.1126/scitranslmed.aaf1938
PubMed id: 27147589
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