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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, 2017.
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© Copyright 2017 The Authors, some rights reserved. Nonalcoholic fatty liver disease (NAFLD) is now the most common progressive liver disease in developed countries and is the second leading indication for liver transplantation due to the extensive fibrosis it causes. NAFLD progression is thought to be tied to chronic low-level type 1 inflammation originating in the adipose tissue during obesity; however, the specific immunological mechanisms regulating the progression of NAFLD-associated fibrosis in the liver are unclear. To investigate the immunopathogenesis of NAFLD more completely, we investigated adipose dysfunction, nonalcoholic steatohepatitis (NASH), and fibrosis in mice that develop polarized type 1 or type 2 immune responses. Unexpectedly, obese interleukin-10 (IL-10)/IL-4-deficient mice (type 1-polarized) were highly resistant to NASH. This protection was associated with an increased hepatic interferon-g (IFN-g) signature. Conversely, IFN-γ- deficient mice progressed rapidly to NASH with evidence of fibrosis dependent on transforming growth factor-β (TGF-β) and IL-13 signaling. Unlike increasing type 1 inflammation and the marked loss of eosinophils seen in expanding adipose tissue, progression of NASH was associated with increasing eosinophilic type 2 liver inflammation in mice and human patient biopsies. Finally, simultaneous inhibition of TGF-β and IL-13 signaling attenuated the fibrotic machinery more completely than TGF-β alone in NAFLD-associated fibrosis. Thus, although type 2 immunity maintains healthy metabolic signaling in adipose tissues, it exacerbates the progression of NAFLD collaboratively with TGF-β in the liver.
Author(s): Hart KM, Fabre T, Sciurba JC, Gieseck RL, Borthwick LA, Vannella KM, Acciani TH, De Queiroz Prado R, Thompson RW, White S, Soucy G, Bilodeau M, Ramalingam TR, Arron JR, Shoukry NH, Wynn TA
Publication type: Article
Publication status: Published
Journal: Science Translational Medicine
Year: 2017
Volume: 9
Issue: 396
Print publication date: 28/06/2017
Online publication date: 28/06/2017
Acceptance date: 02/04/2016
Date deposited: 14/05/2020
ISSN (print): 1946-6234
ISSN (electronic): 1946-6242
Publisher: American Association for the Advancement of Science
URL: http://stm.sciencemag.org/content/9/396/eaal3694
DOI: 10.1126/scitranslmed.aal3694
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