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Innate immune signaling and specifically NF\u03baB activation play a complex role in mediating the hepatic response to toxic APAP exposures. While inflammatory innate immune responses contribute to APAP\u2010induced injury, these same pathways play a role in regeneration and repair. Previous studies have shown that attenuating I\u03baB\u03b2\/NF\u03baB signaling downstream of TLR4 activation can limit injury, but whether this pathway contributes to APAP\u2010induced hepatic injury is unknown. We hypothesized that the absence of I\u03baB\u03b2\/NF\u03baB signaling in the setting of toxic APAP exposure would attenuate APAP\u2010induced hepatic injury. To test this, we exposed adult male WT and I\u03baB\u03b2<jats:sup>\u2212\/\u2212<\/jats:sup> mice to APAP (280\u2009mg\/kg, IP) and evaluated liver histology at early (2\u201324\u2009hr) and late (48\u201372\u2009hr) time points. Furthermore, we interrogated the hepatic expression of NF\u03baB inflammatory (<jats:italic>Cxcl1<\/jats:italic>, <jats:italic>Tnf<\/jats:italic>, <jats:italic>Il1b<\/jats:italic>, <jats:italic>Il6<\/jats:italic>, <jats:italic>Ptgs2<\/jats:italic>, and <jats:italic>Ccl2<\/jats:italic>), anti\u2010inflammatory (<jats:italic>Il10<\/jats:italic>, <jats:italic>Tnfaip3<\/jats:italic>, and <jats:italic>Nfkbia<\/jats:italic>), and Nrf2\/antioxidant (<jats:italic>Gclc<\/jats:italic>, <jats:italic>Hmox<\/jats:italic>, and <jats:italic>Nqo1<\/jats:italic>) target genes previously demonstrated to play a role in APAP\u2010induced injury. Conflicting with our hypothesis, we found that hepatic injury was similar in WT and I\u03baB\u03b2<jats:sup>\u2212\/\u2212<\/jats:sup> mice. Acutely, the induced expression of some target genes was similar in WT and I\u03baB\u03b2<jats:sup>\u2212\/\u2212<\/jats:sup> mice (<jats:italic>Tnfaip3<\/jats:italic>, <jats:italic>Nfkbia<\/jats:italic>, and <jats:italic>Gclc<\/jats:italic>), while others were either not induced (<jats:italic>Cxcl1<\/jats:italic>, <jats:italic>Tnf<\/jats:italic>, <jats:italic>Ptgs2<\/jats:italic>, and <jats:italic>Il10<\/jats:italic>) or significantly attenuated (<jats:italic>Ccl2<\/jats:italic>) in I\u03baB\u03b2<jats:sup>\u2212\/\u2212<\/jats:sup> mice. At later time points, APAP\u2010induced hepatic expression of <jats:italic>Il1b<\/jats:italic>, <jats:italic>Il6<\/jats:italic>, and <jats:italic>Gclc<\/jats:italic> was significantly attenuated in I\u03baB\u03b2<jats:sup>\u2212\/\u2212<\/jats:sup> mice. Based on these findings, the therapeutic potential of targeting I\u03baB\u03b2\/NF\u03baB signaling to treat toxic APAP\u2010induced hepatic injury is likely limited.<\/jats:p>","DOI":"10.1002\/ar.25126","type":"journal-article","created":{"date-parts":[[2022,11,25]],"date-time":"2022-11-25T05:26:49Z","timestamp":1669354009000},"page":"1251-1264","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Absence of <scp>I\u03baB\u03b2<\/scp>\/<scp>NF\u03baB<\/scp> signaling does not attenuate acetaminophen\u2010induced hepatic injury"],"prefix":"10.1002","volume":"308","author":[{"given":"Mack","family":"Solar","sequence":"first","affiliation":[{"name":"Section of Neonatology, Department of Pediatrics University of Colorado School of Medicine  Aurora Colorado USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maya R.","family":"Grayck","sequence":"additional","affiliation":[{"name":"Section of Neonatology, Department of Pediatrics University of Colorado School of Medicine  Aurora Colorado USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William C.","family":"McCarthy","sequence":"additional","affiliation":[{"name":"Section of Neonatology, Department of Pediatrics University of Colorado School of Medicine  Aurora Colorado USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lijun","family":"Zheng","sequence":"additional","affiliation":[{"name":"Section of Neonatology, Department of Pediatrics University of Colorado School of Medicine  Aurora Colorado USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oscar A.","family":"Lacayo","sequence":"additional","affiliation":[{"name":"Section of Neonatology, Department of Pediatrics University of Colorado School of Medicine  Aurora Colorado USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura G.","family":"Sherlock","sequence":"additional","affiliation":[{"name":"Section of 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