Plasmin activity and sterile inflammation synergize to promote lethal embryonic liver degeneration

Embryonic livers undergo extensive vascular expansion after midgestation to support their rapid growth and evolving functions. Immature embryonic vessels are structurally supported by extracellular matrix (ECM), which is also critical for normal liver development and function. During this same period, pro-inflammatory cytokines that function to promote hematopoiesis and hepatic organogenesis must be tightly regulated to prevent sterile inflammation. However, the contributions of endothelial cells to ECM and cytokine production during embryonic liver development are still poorly understood. Here we explore how the epigenetic chromatin-remodeling enzymes CHD4 and BRG1 work antagonistically in embryonic endothelial cells to protect developing livers from lethal degeneration. Our transcriptomic analysis of endothelial Chd4 mutant livers, which undergo degeneration after midgestation, indicated an upregulation of both the ECM protease plasmin activity and sterile inflammation prior to the onset of lethal hepatic phenotypes. Within these pathways, we found that endothelial CHD4 and BRG1 antagonistically regulated transcription of the plasmin activator uPAR and of the inflammatory adhesion molecule ICAM-1 in developing livers. Importantly, elevated plasmin activity and sterile inflammation synergistically contribute to hepatic degeneration because a combination of genetic plasminogen reduction and treatment with the anti-inflammatory drug carprofen reduced Chd4 mutant liver phenotypes more effectively than plasminogen deficiency or carprofen alone. Our findings highlight the critical role of endothelial cells in transcriptionally modulating plasmin activity and sterile inflammation and demonstrate the detrimental synergy of these pathways during liver development.