Critical role of OX40 in drug-induced acute liver injury

The innate and adaptive immune systems both play important roles in drug-induced liver injury (DILI). However, the crosstalk between the innate and adaptive immunity in DILI is largely unknown. Extensive crosstalk is likely mandated by co-stimulatory interactions between these immune systems. OX40 is a co-stimulatory molecule, but whether it regulates the intrahepatic immune response in DILI remains unknown. Experimental approach: Acute liver injury was induced by paracetamol (acetaminophen), carbon tetrachloride (CCl4 ), and d-galactosamine/LPS (GalN/LPS) in wild-type (WT) and Ox40 knockout (KO) mice, and disease progress was compared. Key

The innate and adaptive immune systems both play important roles in drug-induced liver injury (DILI). However, the crosstalk between the innate and adaptive immunity in DILI is largely unknown. Extensive crosstalk is likely mandated by co-stimulatory interactions between these immune systems. OX40 is a co-stimulatory molecule, but whether it regulates the intrahepatic immune response in DILI remains unknown. Experimental approach: Acute liver injury was induced by paracetamol (acetaminophen), carbon tetrachloride (CCl4 ), and d-galactosamine/LPS (GalN/LPS) in wild-type (WT) and Ox40 knockout (KO) mice, and disease progress was compared. Key

Plasma OX40 levels were significantly increased and were augmented in intrahepatic CD4+ T cells after paracetamol, CCl4 , or GalN/LPS administration. Liver injury in Ox40-deficient mice was attenuated compared with that in WT mice. Compared with WT mice, hepatic infiltration of Th1 and Th17 cells and macrophages in Ox40 KO mice was reduced. Furthermore, adoptive transfer of Ox40 KO-CD4+ T cells to Rag1-/- mice resulted in alleviated liver injury compared with WT-CD4+ T-cell transfer, with reduced liver infiltration of macrophages and pro-inflammatory cytokine secretion. Moreover, OX40/Fc stimulation in vitro revealed that soluble OX40 enhanced the biological function of murine macrophages, including up-regulation of genes associated with inflammation and tissue infiltration. Finally, soluble OX40 levels were significantly elevated in DILI patients compared with healthy controls.