Research ArticleFibrosis

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

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Science Translational Medicine  28 Jun 2017:
Vol. 9, Issue 396, eaal3694
DOI: 10.1126/scitranslmed.aal3694

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Opposing cytokines in obesity and fibrosis

Polarized cytokine networks can drive immunopathogenesis forward. Obesity that leads to liver fibrosis involves type 1 cytokines, so Hart et al. expected obese mice prone to type 1 cytokine responses to experience more pronounced fibrosis. Instead, they saw that these mice were resistant to steatohepatitis. Fibrotic livers from mice and human biopsies showed type 2 inflammation and recruitment of eosinophils, unlike the inflammation observed in the adipose tissue during obesity. These findings reveal that cytokine activity that is beneficial for the homeostasis of one tissue can be detrimental to another.

Abstract

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-γ (IFN-γ) 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.

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