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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13 Scopus citations

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
StatePublished - Aug 23 2016

ASJC Scopus subject areas

  • General

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    Qiu, Z., Cervantes, J. L., Cicek, B. B., Mukherjee, S., Venkatesh, M., Maher, L. A., Salazar, J. C., Mani, S., & Khanna, K. M. (2016). Pregnane X receptor regulates pathogen-induced inflammation and host defense against an intracellular bacterial infection through toll-like receptor 4. Scientific reports, 6, [31936]. https://doi.org/10.1038/srep31936