The role of MMP12 in stage-specific pro-regenerative effect of macrophages during liver fibrosis

The development of liver fibrosis is a coordinated process accompanied by chronic inflammation and an abnormal consequence of tissue injury repair response characterized by scar formation. In this study, using carbon tetrachloride (CCl4)-induced liver fibrosis mice model, we profiled the kinetic change of the number and spatial distribution of macrophages (Mø) in different phase during the progression of liver fibrosis. In addition, we found early injury stage (within the first week after CCl4 treatment) is the crucial phase for control the progression of liver fibrosis, since robust liver regeneration was observed only during the early stage (acute inflammatory phase). Furthermore, we proved Møduring early stage (E-Mø) are responsible for maintaining liver regeneration niche and protecting liver from CCl4- induced necrosis instead of Mø during late fibrotic stage (L-Mø). Consequently, the depletion of E-Mø accelerates liver fibrosis progression. We performed a heatmap analysis of related transcript profiles and observed the enriched expression of Mmp12 in E-Mø, compared to normal hepatic Mø and L-Mø. This finding ultimately drives a pro-regenerative program that is essential for timely liver tissue repair and the alleviation liver fibrosis. Taken together, we identified the dynamic evolution of Mø during liver fibrosis and Mmp12+/hi E-Mø is critical component for maintaining early liver regeneration niche and suppressing late fibrotic process.