Pregnane X receptor regulates pathogen-induced inflammation and host defense against an intracellular bacterial infection through toll-like receptor 4

Zhijuan Qiu, Jorge L. Cervantes, Basak B. Cicek, Subhajit Mukherjee, Madhukumar Venkatesh, Leigh A. Maher, Juan C. Salazar, Sridhar Mani, Kamal M. Khanna

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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.

Original languageEnglish (US)
Article number31936
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - Aug 23 2016

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