title: Pregnane X Receptor Regulates Pathogen-Induced Inflammation and Host Defense against an Intracellular Bacterial Infection through Toll-like Receptor 4.
abstract: The nuclear pregnane X receptor (PXR) plays a central role in regulating xenobiotic metabolism. We now report a novel role for PXR as a critical negative regulator of innate immunity after infection. Pxr(-/-) mice exhibited remarkably elevated pro-inflammatory cytokine and chemokine production following infection with Listeria monocytogenes (Lm). Despite the more robust innate immune response, Pxr(-/-) mice were highly susceptible to Lm 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 Lm in Pxr(-/-) mice. Mechanistically, the heightened inflammation in Pxr(-/-) mice resulted in the death of inflammatory monocytes that led to the enhanced susceptibility to Lm infection. These data demonstrated that PXR regulated pathogen-induced inflammation and host defense against Lm 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.
authors.affiliation: Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, USA.
authors.forename: Zhijuan
authors.initials: Z
authors.lastname: Qiu
authors.affiliation: Department of Pediatrics, University of Connecticut Health Center, Farmington, CT 06030, USA.
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Cervantes
authors.affiliation: Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, USA.
authors.forename: Basak B
authors.initials: BB
authors.lastname: Cicek
authors.affiliation: Departments of Genetics and Medicine, Albert Einstein College of Medicine, Bronx, NY10461, USA.
authors.forename: Subhajit
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Departments of Genetics and Medicine, Albert Einstein College of Medicine, Bronx, NY10461, USA.
authors.forename: Madhukumar
authors.initials: M
authors.lastname: Venkatesh
authors.affiliation: Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, USA.
authors.forename: Leigh A
authors.initials: LA
authors.lastname: Maher
authors.affiliation: Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, USA.|Department of Pediatrics, University of Connecticut Health Center, Farmington, CT 06030, USA.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Salazar
authors.affiliation: Departments of Genetics and Medicine, Albert Einstein College of Medicine, Bronx, NY10461, USA.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Mani
authors.affiliation: Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, USA.|Department of Pediatrics, University of Connecticut Health Center, Farmington, CT 06030, USA.
authors.forename: Kamal M
authors.initials: KM
authors.lastname: Khanna
mesh_terms: D000818:Animals; D055786:Gene Knockout Techniques; D007113:Immunity, Innate; D008089:Listeria monocytogenes / Q000472:pathogenicity*; D008088:Listeriosis / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D009000:Monocytes / Q000378:metabolism; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4