Abstract
Understanding the intrahepatic protective immune systems against acetaminophen (APAP)-induced acute liver injury (ALI) is currently limited. Here we reveal that Gram-positive gut-microbiota-derived pathogen-associated molecular patterns promote the CCL2-dependent infiltration of hepatotoxic Ly6Chi monocytes into the APAP-damaged liver, thus inducing APAP-ALI. Conversely, Gram-negative bacterial pathogen-associated molecular patterns activate hepatic CD103⁺ cDC1s to produce IL-15, which in turn expands intrahepatic tissue-resident memory CD8⁺ T (TRM) cells and promotes protective immunity against APAP-derived liver injury. APAP-ALI was further exacerbated in Batf3-knockout and Rag1-knockout mice owing to an increased population of intrahepatic Ly6Chi monocytes in both knockout strains. The adoptive transfer of hepatic CD8+ T cells or hepatic CD103+ cDC1s from wild-type mice ameliorated APAP-ALI in both knockout mice. Notably, CD44+CD69+ TRM cells within hepatic CD8+ T cells, when activated by IL-15/IL-15Rα from hepatic CD103+ cDC1s of APAP mice, played a crucial role in inducing apoptosis of liver-infiltrating monocytes through direct cell-to-cell interactions and granzyme B secretion. Human results supported these animal findings. Our findings underscore the existence of an intrahepatic protective immune system, the hepatic CD103+ cDC1/CD8+ TRM axis, which regulates APAP-ALI by controlling pathogenic monocytes.