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However, the crosstalk between the innate and adaptive immunity in DILI is largely unknown. Extensive crosstalk is likely mandated by co\u2010stimulatory interactions between these immune systems. OX40 is a co\u2010stimulatory molecule, but whether it regulates the intrahepatic immune response in DILI remains unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Acute liver injury was induced by paracetamol (acetaminophen), carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>), and <jats:sc>d<\/jats:sc>\u2010galactosamine\/LPS (GalN\/LPS) in wild\u2010type (WT) and <jats:italic>Ox40<\/jats:italic> knockout (KO) mice, and disease progress was compared.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Plasma OX40 levels were significantly increased and were augmented in intrahepatic CD4<jats:sup>+<\/jats:sup> T cells after paracetamol, CCl<jats:sub>4<\/jats:sub>, or GalN\/LPS administration. Liver injury in <jats:italic>Ox40<\/jats:italic>\u2010deficient mice was attenuated compared with that in WT mice. Compared with WT mice, hepatic infiltration of Th1 and Th17 cells and macrophages in <jats:italic>Ox40<\/jats:italic> KO mice was reduced. Furthermore, adoptive transfer of <jats:italic>Ox40<\/jats:italic> KO\u2010CD4<jats:sup>+<\/jats:sup> T cells to <jats:italic>Rag1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice resulted in alleviated liver injury compared with WT\u2010CD4<jats:sup>+<\/jats:sup> T\u2010cell transfer, with reduced liver infiltration of macrophages and pro\u2010inflammatory cytokine secretion. Moreover, OX40\/Fc stimulation in vitro revealed that soluble OX40 enhanced the biological function of murine macrophages, including up\u2010regulation of genes associated with inflammation and tissue infiltration. Finally, soluble OX40 levels were significantly elevated in DILI patients compared with healthy controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>OX40 is a key molecule that promotes both pro\u2010inflammatory macrophage and CD4<jats:sup>+<\/jats:sup> T\u2010cell function, exacerbating paracetamol\u2010induced liver injury. OX40 could serve as a diagnostic index and therapeutic target of DILI.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15041","type":"journal-article","created":{"date-parts":[[2020,3,5]],"date-time":"2020-03-05T06:15:49Z","timestamp":1583388949000},"page":"3183-3196","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Critical role of OX40 in drug\u2010induced acute liver injury"],"prefix":"10.1111","volume":"177","author":[{"given":"Chunpan","family":"Zhang","sequence":"first","affiliation":[{"name":"General Surgery Department, Beijing Friendship Hospital Capital Medical University  Beijing China"},{"name":"Liver Research Center, Beijing Friendship Hospital Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Jin","sequence":"additional","affiliation":[{"name":"General Surgery Department, Beijing Friendship Hospital Capital Medical University  Beijing 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