PD1 expression inhibits hepoatic inflammation and fibrosis in non-alcoholic steatohepatitis

PD-L1 is a B7-family member that binds to programmed death-1 (PD-1). PD-1 is involved in the negative regulation of immune responses. Recently, we have shown that PD-L1 is expressed on hepatocytes, and that hepatocytes induce apoptosis in T-cells via PD-L1. The aim of this study was to analyzed the expression and function of PD-1 in non-alcoholic steatohepatitis (NASH) in which T-cells play an important pathophysiological role according to most recent studies. Methods and Results: Two different NASH-models were applied to (i) PD-1 deficient (PD1-ko), (ii) PD-1 transgenic (PD1-trg), and (iii) wildtype (wt) control mice. Both models led to significant hepatic inflammation, and also PD-L1 and PD-1 upregulated in wt-mice. Noteworthy, hepatocellular inflammation and apoptosis were significantly lower in PD1-trg mice, but significantly higher in PD1-ko mice. Histopathological analysis confirmed extended hepatocellular damage and fibrosis in PD1-ko mice compared to wt-mice, while the damage in PD1-trg mice was less pronounced. Analysis of human hepatic specimens confirmed increased expression of PD-L1 and PD-1 in NASH-patients. Moreover, we observed increased PD-L1 expression in primary human hepatocytes in an in vitro model of hepatocellular lipid accumulation. Conclusion: Our findings indicate that increased hepatic PD-L1 expression in steatotic livers exhibits a protective effect via PD1. The control of this interaction appears as a promising strategy to inhibit NASH development and progression. Further, hepatic PD-L1/PD-1 expression may serve as prognostic marker.