Dual Immune Lineage Activation Underlies Systemic Immunopathology in Acute-on-Chronic Liver Failure

Acute-on-chronic liver failure (ACLF) is a rapidly progressive syndrome characterized by acute hepatic decompensation in the setting of chronic liver disease and frequently accompanied by multi-organ dysfunction/failure and high short-term mortality. Although a dysregulated immunity (immunopathology) is increasingly recognized as a central driver of ACLF pathogenesis, the mechanistic basis linking immune activation to systemic organ injury remains poorly defined, in part due to the lack of a preclinical model that faithfully recapitulates immune-mediated organ damage. Here, a combined carbon tetrachloride/acetaminophen/lipopolysaccharide model (CALPS) was used that integrates chronic hepatotoxic injury with acute metabolic (acetaminophen) and inflammatory (lipopolysaccharide) stressors to reproduce key clinical and immunologic features of ACLF. CALPS mice developed severe hepatic injury, advanced fibrosis, and marked systemic inflammation. Comprehensive immunophenotyping revealed concurrent activation of myeloid and lymphoid lineages, accompanied by extensive infiltration of neutrophils, monocytes/macrophages, and T lymphocytes into the liver and extrahepatic organs, including kidney, lung, and heart. These immune abnormalities were specific to ACLF and absent in chronic liver disease, acute liver failure, and control cohorts. Notably, renal dysfunction correlated strongly with immune cell infiltration, supporting a mechanistic link between pathologic immune activation and multi-organ failure. Collectively, the CALPS model provides a robust and translational platform to investigate immune-mediated organ injury in ACLF and to advance targeted immunomodulatory therapies.