Immune Modulation of NAFLD progression to NASH and Hepatic Fibrosis in Obesity

FARE Award Winner

Authors

• KM Hart
• RL Gieseck
• LA Borthwick
• KM Vannella
• RW Thompson
• S White
• JC Sciurba
• TR Ramalingam
• TA Wynn

Abstract

Worldwide incidence of obesity has attained epidemic proportions, putting an estimated 300-500 million people at risk for the myriad of health concerns termed the metabolic syndrome. This includes non-alcoholic fatty liver disease (NAFLD) and its pathophysiologic spectrum of non-alcoholic steatohepatitis(NASH) and cirrhosis, characterized by hepatic fat accumulation(steatosis), immune infiltration, and eventual scarring, or fibrosis, of the liver. While progression of NAFLD appears to be intricately tied to chronic low-level type-1 inflammation originating in the adipose tissue, the specific immunological mechanisms underlying progression to NASH and cirrhosis are poorly understood. We hypothesized that elimination of type-1 cytokines in obesity would attenuate disease. However, interferon gamma (IFN-gamma) knockout mice on a high fat diet(HFD) had increased steatosis and rapidly progressed to NASH with evidence of fibrosis. Unlike the switch to type-1 inflammation and loss of adipose resident eosinophils observed in expanding adipose tissue, NAFLD progression was associated with mixed inflammation, eosinophilic infiltration and altered regulation of the profibrotic mediators IL-13 and transforming growth factor beta(TGF-b). Antibody blockade of TGF-beta in a chronic HFD NASH model attenuated expression of some fibrosis-associated extracellular matrix proteins including collagen, but increased serum liver enzymes and markers of type-2 inflammation. IFN-gamma-/- mice recapitulated these findings, revealing a role for regulation of type-2 inflammation in controlling fibrosis. Thus, rather than driving metabolic disease as has been described in adipose tissue, our data reveal a protective role for some pro-inflammatory cytokines in NAFLD progression and demonstrate divergent roles for TGF-beta in NASH and cirrhosis.

Scientific Focus Area: Immunology

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