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

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.

γδ T Cells Promote Steatohepatitis by Orchestrating Innate and Adaptive Immune Programming

“…IFN-γ has been shown to confer protection against chronic liver diseases. (21,22) Further, consistent with our in vivo observations, liver γδT cells mitigated CD4 + T-cell expression of IFN-γ in coculture experiments (Fig. 6E).…”

“…We recently showed that γδT cells direct T‐helper cell effector function in cancer by checkpoint receptor ligation . Similarly, in the presence of γδT cells, hepatic CD4 + T cells lower levels of cytokines, such as IFN‐γ, that have protective roles in SH . Accordingly, our in vitro data show that hepatic γδT cells mitigate CD4 + T cell IFN‐γ production.…”

“…(11) Similarly, in the presence of γδT cells, hepatic CD4 + T cells lower levels of cytokines, such as IFN-γ, that have protective roles in SH. (21,22,45) Accordingly, our in vitro data show that hepatic γδT cells mitigate CD4 + T cell IFN-γ production. Of note, in other models of liver disease, IFN-γ has been shown to induce liver injury and inflammation.…”

Hepatic NK cells attenuate fibrosis progression of non‐alcoholic steatohepatitis in dependent of CXCL10‐mediated recruitment

“…Consistently, increased production of IFN‐γ in intrahepatic NK cells was detected during MCD‐induced NASH (Figure C), and expression levels of IFN‐γ in the liver were significantly decreased upon the depletion of NK cells (Figure C). A recent study also reported the protective role of IFN‐γ in the NASH with obesity . However, the production of TGF‐β and IL‐10 was also upregulated in the intrahepatic NK cells (Figure C).…”

“…However, the production of TGF‐β and IL‐10 was also upregulated in the intrahepatic NK cells (Figure C). TGF‐β signalling in hepatocytes contributed to hepatocyte death and lipid accumulation via Smad signalling and ROS production that promoted the development of NASH and NASH progression to fibrosis . The roles of these cytokines should be further investigated to elucidate the mechanisms underlying the role of NK cells in NASH.…”