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We now report a novel role for PXR as a critical negative regulator of innate immunity after infection. <jats:italic>Pxr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice exhibited remarkably elevated pro-inflammatory cytokine and chemokine production following infection with <jats:italic>Listeria monocytogenes<\/jats:italic> (<jats:italic>Lm<\/jats:italic>). Despite the more robust innate immune response, <jats:italic>Pxr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice were highly susceptible to <jats:italic>Lm<\/jats:italic> infection. Surprisingly, disruption of the Toll-like receptor 4 (TLR4) but not TLR2 signaling restored the inflammation to normal levels and the ability to clear <jats:italic>Lm<\/jats:italic> in <jats:italic>Pxr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice. Mechanistically, the heightened inflammation in <jats:italic>Pxr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice resulted in the death of inflammatory monocytes that led to the enhanced susceptibility to <jats:italic>Lm<\/jats:italic> infection. These data demonstrated that PXR regulated pathogen-induced inflammation and host defense against <jats:italic>Lm<\/jats:italic> infection through modulating the TLR4 pathway. In summary, we discovered an apical role for PXR in regulating innate immunity. In addition, we uncovered a remarkable negative impact of the TLR4 pathway in controlling the quality of the inflammatory response and host defense against a gram-positive bacterial infection.<\/jats:p>","DOI":"10.1038\/srep31936","type":"journal-article","created":{"date-parts":[[2016,8,23]],"date-time":"2016-08-23T09:39:14Z","timestamp":1471945154000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Pregnane X Receptor Regulates Pathogen-Induced Inflammation and Host Defense against an Intracellular Bacterial Infection through Toll-like Receptor 4"],"prefix":"10.1038","volume":"6","author":[{"given":"Zhijuan","family":"Qiu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jorge L.","family":"Cervantes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Basak B.","family":"Cicek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Subhajit","family":"Mukherjee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madhukumar","family":"Venkatesh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leigh A.","family":"Maher","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan C.","family":"Salazar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sridhar","family":"Mani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kamal M.","family":"Khanna","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2016,8,23]]},"reference":[{"key":"BFsrep31936_CR1","doi-asserted-by":"publisher","first-page":"e001","DOI":"10.1621\/nrs.07001","volume":"7","author":"C Zhou","year":"2009","unstructured":"Zhou, C., Verma, S. & Blumberg, B. 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