ATF3 modulates the extracellular microenvironment and inflammation pathways, protecting the mouse liver from carbon tetrachloride (CCl4)-induced fibrosis

Introduction Liver fibrosis is a pathological process characterized by the excessive proliferation of connective tissue within the liver. Hepatic stellate cells (HSCs) are very important in fibrogenesis and are regulated by liver macrophages. Activating transcription factor 3 (ATF3) is critical in various inflammatory processes; however, its specific role in macrophage-mediated mechanisms of liver fibrosis remains largely unexplored.

Methods We investigated the role of ATF3 in liver fibrogenesis using mice with bone marrow macrophage-specific ATF3 knockout (ATF3-Δmyel). Mice were treated with intraperitoneal injections of CCl4. Immunohistochemistry (IHC) was used to assess the infiltration of different macrophage populations in liver tissue. Furthermore, we analyzed effector molecules and signaling pathways associated with the differences in fibrosis between the two groups.

Results Our data showed that liver fibrosis is more severe in ATF3-Δmyel mice. Based on our IHC results we found that the proportion of liver resident macrophages versus monocyte-derived macrophages changed. We observed a decrease in the expression of Kupffer cell in the ATF3-Δmyel group, at the same time, the expression of monocyte-derived macrophages increased. By analyzing potential effector molecules, we found that the liver tissue of the ATF3-Δmyel group had higher expression of chemokines. Pathway analysis showed that it was mainly the TGF-β/Smad pathway that seemed to be affected.

Discussion We were able to show the strong influence of ATF3 on macrophages and liver fibrosis. ATF3 has a crucial impact on recruitment and inflammatory activation of bone marrow-derived macrophages, thereby altering the severity of liver fibrosis.

Key words Liver fibrosis; macrophage; ATF3

Publication History

Article published online:
20 January 2025