Aging aggravates acetaminophen-induced acute liver injury and inflammation through inordinate C/EBPα-BMP9 crosstalk

Background Previous studies have shown that bone morphogenetic protein 9 (BMP9) is almost exclusively produced in the liver and reaches tissues throughout the body as a secreted protein. However, the mechanism of BMP9 action and its role in aging-associated liver injury and inflammation are still unclear. Results Aging significantly aggravates acetaminophen (APAP)-induced acute liver injury (ALI). Increased expression of CCAAT/enhancer binding protein a (C/EBPa) and BMP9 was identified in aged livers and in hepatocytes and macrophages (M phi s) isolated from aged mice. Further analysis revealed that excess BMP9 was directly related to APAPinduced hepatocyte injury and death, as evidenced by activated drosophila mothers against decapentaplegic protein 1/5/9 (SMAD1/5/9) signaling, an increased dead cell/total cell ratio, decreased levels of ATG3 and ATG7, blocked autophagy, increased senescence-associated beta-galactosidase (SA-beta-Gal) activity, and a higher rate of senescenceassociated secretory phenotype (SASP) acquisition. In contrast, Bmp9 knockout (Bmp9(-/-)) partially alleviated the aforementioned manifestations of BMP9 overexpression. Moreover, BMP9 expression was found to be regulated by C/EBPa in vitro and in vivo. Notably, BMP9 also downregulated autophagy through its effect on autophagy-related genes (ATG3 and ATG7) in MFs, which was associated with aggravated liver injury and SASP acquisition. Conclusions In summary, the present study highlights the crucial roles played by C/EBPa-BMP9 crosstalk and provides insights into the interrelationship between hepatocytes and MFs during acute liver injury.