ATRA-mediated-crosstalk between stellate cells and Kupffer cells inhibits autophagy and promotes NLRP3 activation in acute liver injury

The crosstalk between hepatic stellate cells (HSCs) and Kupffer cells (KCs) is involved in acute liver injury (ALI). Meanwhile, the change of lipid droplet in HSCs predicts the development of ALI. However, it is not clear whether all trans retinoic acid (ATRA), as one of the important products of lipid droplet metabolism from HSC, regulate the activation of KCs. Firstly, our results confirmed that ATRA release and IL-113 production were significantly increased in a CCl4-induced model of ALI. In addition, we observed that ATRA could induce KCs to produce IL-113 through retinoic acid receptor (RAR) in vitro. Further mechanism studies confirmed that RAR could promote priming of NLRP3 inflammasome through transcriptional activation. ATRA also blocked autophagic flow by activating the AKT/mTOR pathway, leading to an excessive accumulation of ROS, which further activated the NLRP3 inflammasome. Activated NLRP3 inflammasome caused pyroptosis of macrophages and explosive release of IL-113. In conclusion, we have uncovered a novel crosstalk pattern between HSCs and KCs, and ATRAmediated-crosstalk between HSCs and KCs inhibits autophagy and promotes NLRP3 activation to aggravate acute liver injury.