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Type 2 immunity is protective in metabolic disease but exacerbates NAFLD collaboratively with TGF-β

Lookup NU author(s): Dr Lee Borthwick

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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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Abstract

© 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.


Publication metadata

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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