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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gene Knockout Techniques
  • Immunity, Innate
  • Listeria monocytogenes / pathogenicity*
  • Listeriosis / immunology*
  • Listeriosis / metabolism
  • Listeriosis / microbiology
  • Mice
  • Monocytes / metabolism
  • Pregnane X Receptor
  • Receptors, Steroid / genetics*
  • Receptors, Steroid / metabolism
  • Signal Transduction
  • Toll-Like Receptor 2 / metabolism
  • Toll-Like Receptor 4 / metabolism*

Substances

  • Pregnane X Receptor
  • Receptors, Steroid
  • Tlr2 protein, mouse
  • Tlr4 protein, mouse
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4