Nonalcoholic fatty liver disease (NAFLD) affects 80% of obese (OB) patients. NAFLD progression to nonalcoholic steatohepatitis (NASH) involves inflammation and development of fibrosis. Innate immune system activation is a key feature of inflammation in NASH; however, the link between innate immune system components and liver fibrosis is unclear. Recent evidence suggests that eosinophils (EOS) augment the progression of fibrotic liver disease in mice on a high fat diet (HFD).
We hypothesize that independently of HFD, EOS and associated type 2 (Th2) mediators initiate and maintain hepatic fibrosis. To this end, we evaluated hepatic fibrosis, EOS presence, and mRNA levels of Th2 markers in the livers of transgenic mice with eosinophilia (IL5Tg) vs wild type littermates (WT) on chow diet.
Compared to WT livers, IL5Tg mice showed an increase in EOS infiltration and revealed significant hepatic fibrosis. Fibrotic areas were surrounded by a large accumulation of EOS. Furthermore, mRNA levels of IL4, IL13, and Resistin like alpha (Retnlα) were significantly elevated in IL5Tg livers. Thus, hepatic overexpression of EOS induces the development of liver fibrosis in rodents. Next, we hypothesize EOS play a similar important role in NASH patients. Liver biopsies of 14 OB patients with hepatic fibrosis (METAVIR F>2) were compared to 14 OB patients without fibrosis (METAVIR F=0) for EOS content by immunohistochemistry. Subjects were matched for age, gender, and BMI. Th2 cytokine plasma levels were evaluated in all patients. The livers of F>2 NASH patients revealed a marked increase in EOS, notably in areas of fibrosis. Plasma levels of Th2 mediators were significantly elevated in F>2 patients.
We show that independent of BMI, hepatic EOS associate with hepatic fibrosis in humans. Altogether our data suggest a pivotal role of EOS and related Th2 cytokines in the development of hepatic fibrosis. Future studies need to elucidate the mechanisms linking EOS to fibrosis development.