Liver sinusoidal endothelial cells secret C-X-C motif chemokine ligand 10 to promote the recruitment of invariant NKT cells in acetaminophen-induced liver injury

Drug-induced liver injury (DILI) has become a significant public health concern. Liver sinusoidal endothelial cells (LSECs), serving as the primary defense barrier in the liver, play a crucial role in maintaining the sinusoidal microenvironment. However, the adaptive changes occurring in LSECs and the mechanisms that regulate the immune microenvironment during the initial stages of acetaminophen (APAP)-induced liver injury (AILI) remain unclear. Specifically, a significant knowledge gap remains regarding how LSECs interact with immune cells in AILI. In our study, we observed distinct morphological changes in the LSECs during the early stages of AILI. Using single-nuclear RNA Sequencing, we identified a disease-specific subpopulation of LSECs, characterized by significant enrichment of biological processes associated with vascular remodeling and cell migration following APAP treatment. Simultaneously, APAP enhanced intercellular communication between LSECs and T/NK cells, with an emphasis on invariant natural killer T (iNKT) cells. Specifically, this LSEC population exhibited significant upregulation of CXCL10, a chemokine that plays a pivotal role in the recruitment of hepatic iNKT and CD4⁺ T cells. Pharmacological inhibition of CXCR3, a receptor for CXCL10, using AMG487 effectively blocked the APAP-induced recruitment of these immune cells. In summary, our study elucidates the distinctive alterations in LSECs associated with early AILI and identifies the CXCL10-CXCR3 axis as a critical pathway mediating the recruitment of hepatic iNKT and CD4⁺ T cells. These findings provide valuable insights into the development of novel therapeutic strategies aimed at targeting the CXCL10-CXCR3 signaling axis for the treatment of AILI.

CXCL10; acetaminophen; drug-induced liver injury; invariant natural killer T cell; liver sinusoidal endothelial cell; single-nucleus RNA sequencing.