Chronic liver disease (CLD) is a global health concern due to its potential to lead to serious conditions like hepatocellular carcinoma and liver failure. CLD is characterized by inflammation and fibrosis, with hepatic stellate cells (HSCs) playing a key role in these processes. However, the specific involvement of HSCs in the inflammatory response is not fully understood. A recent study led by researchers at Tokyo Medical and Dental University (TMDU) focused on the role of tumor necrosis factor-α-related protein A20, abbreviated as A20, in this inflammatory signaling.
Previous research has suggested that A20 has anti-inflammatory effects, as shown by severe systemic inflammation in mice lacking this protein. Additionally, genetic variants in the A20 gene are linked to autoimmune hepatitis with cirrhosis. These findings prompted the TMDU team to investigate how A20 functions in HSCs and its potential impact on chronic hepatitis. Using a conditional knockout mouse model where most HSCs lacked A20 expression, along with human HSC cell lines, the researchers uncovered that A20 plays a crucial role in suppressing chronic hepatitis.
Analysis of the livers in the A20-deficient mice revealed spontaneous inflammation and mild fibrosis, indicating the essential role of A20 in preventing chronic hepatitis. RNA sequencing of the mouse HSCs lacking A20 showed patterns of gene expression consistent with inflammation. Furthermore, these cells exhibited abnormal levels of chemokines, which are critical in signaling inflammation. Similar observations were made in human HSC cells, where increased A20 expression led to reduced chemokine levels through the inhibition of the protein DCLK1, which activates the pro-inflammatory JNK signaling pathway.
By inhibiting DCLK1 in cells lacking A20 expression, the researchers were able to significantly reduce chemokine levels, supporting the involvement of A20 in inflammation in HSCs through the DCLK1-JNK pathway. These findings highlight the potential of A20 and DCLK1 as targets for novel therapeutic approaches in treating chronic hepatitis. The study provides valuable insights into the mechanisms underlying inflammation in CLD and sheds light on potential therapeutic strategies for this condition. Further research in this area could lead to the development of more effective treatments for chronic liver diseases.