Senescence of T-Cells Increases with Fibrosis Progression in Chronic Viral Hepatitis

Chronic viral hepatitis is linked to fibrotic liver injury that can progress to liver cirrhosis with its associated complications. Recent evidence suggests a role of senescence in liver fibrosis, although the senescence regulators contributing to fibrosis progression remain unclear. We therefore investigated the role of senescence for fibrosis progression in patients with chronic viral hepatitis. We found a remarkable up-regulation of the cell-cycle inhibitors p21, p27 and p16 and the senescence markers p-HP1γ and γ-H2AX in liver tissues from patients with chronic viral hepatitis compared to healthy liver tissues. Liver tissues with relevant fibrosis stages (F2 – 3) or cirrhosis (F4) revealed a significant increase of senescent cells compared to livers with no or minimal fibrosis (F0 – 1). In cirrhotic livers, a significantly higher number of p-HP1γ, p21 and p27 positive cells was detected compared to liver tissues with F2 – 3 fibrosis. Importantly, we identified T-cells as the dominant cell type contributing to increased senescence during fibrosis progression. Compared to healthy individuals, senescence-associated chitotriosidase activity was significantly elevated in sera from patients with chronic viral hepatitis and correlated with histological fibrosis stages and liver stiffness as assessed by transient elastography.

Conclusions:

Senescence of hepatic T-cells is enhanced in chronic viral hepatitis and increases with fibrosis progression. Serological detection of senescence-associated chitotriosidase might allow for the non-invasive detection of relevant fibrosis stages.