Targeting the PXR-TLR4 signaling pathway to reduce intestinal inflammation in an experimental model of necrotizing enterocolitis

Kezhen Huang, Subhajit Mukherjee, Vera M. Desmarais, Joseph M. Albanese, Ektor Rafti, Andrew Draghi, Leigh A. Maher, Kamal M. Khanna, Sridhar Mani, Adam P. Matson

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

BackgroundThere is substantial evidence that signaling through Toll-like receptor 4 (TLR4) contributes to the pathogenesis of necrotizing enterocolitis (NEC). Pregnane X receptor (PXR), a xenobiotic sensor and signaling intermediate for certain host-bacterial metabolites, has been shown to negatively regulate TLR4 signaling. Here we investigated the relationship between PXR and TLR4 in the developing murine intestine and explored the capacity of PXR to modulate inflammatory pathways involved in experimental NEC.MethodsWild-Type and PXR-/-mice were studied at various time points of development in an experimental model of NEC. In addition, we studied the ability of the secondary bile acid lithocholic acid (LCA), a known PXR agonist in liver, to activate intestinal PXR and reduce NEC-related intestinal inflammation.ResultsWe found a reciprocal relationship between the developmental expression of PXR and TLR4 in wild-Type murine intestine, with PXR acting to reduce TLR4 expression by decreasing TLR4 mRNA stability. In addition, PXR-/-mice exhibited a remarkably heightened severity of disease in experimental NEC. Moreover, LCA attenuated intestinal proinflammatory responses in the early stages of experimental NEC.ConclusionThese findings provide proactive insights into the regulation of TLR4 in the developing intestine. Targeting PXR may be a novel approach for NEC prevention.

Original languageEnglish (US)
Pages (from-to)1031-1040
Number of pages10
JournalPediatric Research
Volume83
Issue number5
DOIs
StatePublished - May 1 2018

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Necrotizing Enterocolitis
Toll-Like Receptor 4
Theoretical Models
Inflammation
Lithocholic Acid
Intestines
pregnane X receptor
RNA Stability
Xenobiotics
Bile Acids and Salts

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

Cite this

Targeting the PXR-TLR4 signaling pathway to reduce intestinal inflammation in an experimental model of necrotizing enterocolitis. / Huang, Kezhen; Mukherjee, Subhajit; Desmarais, Vera M.; Albanese, Joseph M.; Rafti, Ektor; Draghi, Andrew; Maher, Leigh A.; Khanna, Kamal M.; Mani, Sridhar; Matson, Adam P.

In: Pediatric Research, Vol. 83, No. 5, 01.05.2018, p. 1031-1040.

Research output: Contribution to journalArticle

Huang, K, Mukherjee, S, Desmarais, VM, Albanese, JM, Rafti, E, Draghi, A, Maher, LA, Khanna, KM, Mani, S & Matson, AP 2018, 'Targeting the PXR-TLR4 signaling pathway to reduce intestinal inflammation in an experimental model of necrotizing enterocolitis', Pediatric Research, vol. 83, no. 5, pp. 1031-1040. https://doi.org/10.1038/pr.2018.14
Huang, Kezhen ; Mukherjee, Subhajit ; Desmarais, Vera M. ; Albanese, Joseph M. ; Rafti, Ektor ; Draghi, Andrew ; Maher, Leigh A. ; Khanna, Kamal M. ; Mani, Sridhar ; Matson, Adam P. / Targeting the PXR-TLR4 signaling pathway to reduce intestinal inflammation in an experimental model of necrotizing enterocolitis. In: Pediatric Research. 2018 ; Vol. 83, No. 5. pp. 1031-1040.
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abstract = "BackgroundThere is substantial evidence that signaling through Toll-like receptor 4 (TLR4) contributes to the pathogenesis of necrotizing enterocolitis (NEC). Pregnane X receptor (PXR), a xenobiotic sensor and signaling intermediate for certain host-bacterial metabolites, has been shown to negatively regulate TLR4 signaling. Here we investigated the relationship between PXR and TLR4 in the developing murine intestine and explored the capacity of PXR to modulate inflammatory pathways involved in experimental NEC.MethodsWild-Type and PXR-/-mice were studied at various time points of development in an experimental model of NEC. In addition, we studied the ability of the secondary bile acid lithocholic acid (LCA), a known PXR agonist in liver, to activate intestinal PXR and reduce NEC-related intestinal inflammation.ResultsWe found a reciprocal relationship between the developmental expression of PXR and TLR4 in wild-Type murine intestine, with PXR acting to reduce TLR4 expression by decreasing TLR4 mRNA stability. In addition, PXR-/-mice exhibited a remarkably heightened severity of disease in experimental NEC. Moreover, LCA attenuated intestinal proinflammatory responses in the early stages of experimental NEC.ConclusionThese findings provide proactive insights into the regulation of TLR4 in the developing intestine. Targeting PXR may be a novel approach for NEC prevention.",
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AU - Rafti, Ektor

AU - Draghi, Andrew

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