Pregnane x receptor regulates pathogen-induced inflammation and host defense against an intracellular bacterial infection through Toll-like receptor 4
Open accessAbstract
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.
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Combined knockout of Nr1i2 and Tlr4 can rescue the phenotype of Nr1i2−/− mice, possibly by counteracting accelerated cell death of inflammatory monocytes.
“the combined knockout of Nr1i2 and the gene encoding the LPS sensor toll-like receptor 4 (Tlr4) can rescue the phenotype of Nr1i2−/− mice, possibly because it counteracts the accelerated cell death of inflammatory monocytes observed in NR1I2-deficient mice (Z. Qiu et al., 2016; Venkatesh et al., 2014).”
From Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System (2017) · cites this paper as Z. Qiu et al., 2016
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“…the combined knockout of Nr1i2 and the gene encoding the LPS sensor toll-like receptor 4 (Tlr4) can rescue the phenotype of Nr1i2 / mice, possibly because it counteracts the accelerated cell death of inflammatory monocytes observed in NR1I2-deficient mice (Qiu et al., 2016; Venkatesh et al., 2014).”
BackgroundIntestinal epithelial cells: At the interface of the microbiota and mucosal immunity
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- Authors
- Qiu, Z., Cervantes, J. L., Cicek, B. B., Mukherjee, S., Venkatesh, M., Maher, L. A., Salazar, J. C., Mani, S., & Khanna, K. M.
- Affiliations
- UConn Health (US)
- Albert Einstein College of Medicine (US)
- Corresponding author
- Khanna, Kamal M.
- Venue
- Scientific Reports
- Published
- 2016-08-23
- Volume
- 6
- Issue
- 1
- Pages
- 31936-31936
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC4994038
- OpenAlex
- W2516653713
- Cited by
- 46
- References
- 21
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 3 · 2023: 5 · 2022: 8 · 2021: 8 · 2020: 5 · 2019: 5 · 2018: 1 · 2017: 3
- FWCI
- 1.82
- Type
- journal article
- Language
- en
- Update notices
- correction (2017-03-22)
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Crohn's and Colitis Foundation of America (362520)
- Crohn's and Colitis Foundation (362520)
- University of Connecticut Health Center
- National Institutes of Health (UL1TR001073)
- National Cancer Institute (R01CA161879, R01CA127231, P30CA013330)
- National Institute of Allergy and Infectious Diseases (R01AI097375, R01AI090166)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Keywords
- pregnane X receptor, TLR4, Listeria monocytogenes, innate immunity, host defense, intracellular bacterial infection, inflammatory monocytes, inflammatory cytokines, chemokines, TLR2, negative regulation of inflammation
- MeSH terms
- Pregnane X Receptor, Animals, Immunity, Innate, Listeriosis, Listeria monocytogenes, Monocytes, Receptors, Steroid, Signal Transduction, Toll-Like Receptor 2, Toll-Like Receptor 4, Mice, Gene Knockout Techniques
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