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Sci Rep. 2016 Aug 23;6:31936. doi: 10.1038/srep31936.

Pregnane X Receptor Regulates Pathogen-Induced Inflammation and Host Defense against an Intracellular Bacterial Infection through Toll-like Receptor 4.

Author information

1
Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, USA.
2
Department of Pediatrics, University of Connecticut Health Center, Farmington, CT 06030, USA.
3
Departments of Genetics and Medicine, Albert Einstein College of Medicine, Bronx, NY10461, USA.

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.

PMID:
27550658
PMCID:
PMC4994038
DOI:
10.1038/srep31936
[Indexed for MEDLINE]
Free PMC Article

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