ATF3 regulates liver fibrosis by promoting M1 polarization of macrophages

Introduction Liver fibrosis is a pathophysiological proliferation of the liver connective tissue. Hepatic stellate cells (HSCs) play a central role during liver fibrogenesis and they are directly regulated by liver macrophages. Activating transcription factor 3 (ATF3) plays a key role in inflammatory reactions. However, the influence of ATF3 from bone marrow macrophages on the mechanisms of liver fibrosis has not been thoroughly investigated so far.

Methods In this study, we used bone marrow macrophage-specific ATF3 gene knockout mice to study liver fibrogenesis after intraperitoneal injection of CCl4. Firstly, we compared the degree of liver fibrosis between the cohorts. Secondly, we extracted primary mouse bone marrow macrophages and induced them to M1 and M2 phenotypes, respectively. Furthermore, we compared whether ATF3 knockdown affects the polarization of bone marrow macrophages. Finally, we co-cultured polarization-induced M1 macrophages with primary HSCs and determined the expression of α-SMA and Col1a1 in HSCs.

Results Our research shows that liver fibrosis is more severe in ATF3 knockout mice. Studies on primary mouse bone marrow-derived macrophages (BMDM) have found that knockout of ATF3 increases the expression of M1 phenotypic markers meaning that knockout of ATF3 directly targets a profibrotic phenotype. It also influences the activation of HSC while overexpression of ATF3 has the opposite effect.

Discussion There is a strong influence of ATF3 on macrophage polarization and liver fibrosis. These findings might provide some theoretical basis for new therapeutic targets during liver fibrogenesis.

Key words Liver fibrosis; macrophage; polarization; ATF3

Publication History

Article published online:
23 January 2024