Plasmin and sterile inflammation jointly drive fatal embryonic liver degeneration in endothelial chromatin remodeler mutant mice

Embryonic livers undergo extensive vascular expansion after midgestation to support rapid growth and evolving functions. Immature embryonic vessels receive structural support from extracellular matrix (ECM), which is also essential for normal liver development and function. Meanwhile, pro-inflammatory cytokines that promote hematopoiesis and hepatic organogenesis must be tightly regulated to prevent sterile inflammation. However, endothelial contributions to ECM and cytokine production during liver development remain poorly understood. Here, we demonstrate that the chromatin remodelers CHD4 and BRG1 act antagonistically in embryonic endothelial cells to protect developing livers from lethal degeneration. Transcriptomic analysis of endothelial Chd4 mutant livers revealed increased activity of plasmin (an ECM protease) and sterile inflammation before the onset of overt phenotypes. Within these pathways, we found that endothelial CHD4 and BRG1 antagonistically regulate transcription of the plasmin activator uPAR and of the inflammatory adhesion molecule ICAM1 in developing livers. Our genetic and pharmacological data demonstrate that elevated plasmin activity and sterile inflammation synergistically contribute to hepatic degeneration. These findings highlight endothelial transcriptional control of plasmin activity and sterile inflammation and reveal their detrimental synergy during liver development.