Macrophage-derived IL-1β/NF-κB signaling mediates parenteral nutrition-associated cholestasis
| العنوان: | Macrophage-derived IL-1β/NF-κB signaling mediates parenteral nutrition-associated cholestasis |
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| المؤلفون: | Sophie Fillon, Angelo D'Alessandro, Ayed Allawzi, Crystal Woods, Ronald J. Sokol, Sarah McKenna, Padade M. Vue, Carola Dahrenmoeller, Swati Ghosh, Frederick J. Suchy, Karim C. El Kasmi, Michael W. Devereaux, Clyde J. Wright, Julie A. Reisz, Eva Nozik-Grayck, Aimee L. Anderson, Linda K. Johnson, Natarajan Balasubramaniyan |
| المصدر: | Nature Communications Nature Communications, Vol 9, Iss 1, Pp 1-14 (2018) |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Male, Parenteral Nutrition, Interleukin-1beta, General Physics and Astronomy, Receptors, Cytoplasmic and Nuclear, Pharmacology, Enteral administration, Mice, 0302 clinical medicine, Medicine, ABCB11, ATP Binding Cassette Transporter, Subfamily G, Member 5, lcsh:Science, ATP Binding Cassette Transporter, Subfamily B, Member 11, Liver X Receptors, Multidisciplinary, Cholestasis, Caspase 1, NF-kappa B, Sterol transport, Caspases, Initiator, Multidrug Resistance-Associated Protein 2, 3. Good health, Liver, Caspases, 030211 gastroenterology & hepatology, Multidrug Resistance-Associated Proteins, Signal Transduction, Parenteral Nutrition - Associated Cholestasis, Receptors, CCR2, Science, Lipoproteins, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Animals, Humans, Liver X receptor, business.industry, Macrophages, Infant, Newborn, Receptors, Interleukin-1, General Chemistry, medicine.disease, Disease Models, Animal, 030104 developmental biology, Parenteral nutrition, Gene Expression Regulation, Hepatocytes, lcsh:Q, Farnesoid X receptor, business |
| الوصف: | In infants intolerant of enteral feeding because of intestinal disease, parenteral nutrition may be associated with cholestasis, which can progress to end-stage liver disease. Here we show the function of hepatic macrophages and phytosterols in parenteral nutrition-associated cholestasis (PNAC) pathogenesis using a mouse model that recapitulates the human pathophysiology and combines intestinal injury with parenteral nutrition. We combine genetic, molecular, and pharmacological approaches to identify an essential function of hepatic macrophages and IL-1β in PNAC. Pharmacological antagonism of IL-1 signaling or genetic deficiency in CCR2, caspase-1 and caspase-11, or IL-1 receptor (which binds both IL-1α and IL-1β) prevents PNAC in mice. IL-1β increases hepatocyte NF-κB signaling, which interferes with farnesoid X receptor and liver X receptor bonding to respective promoters of canalicular bile and sterol transporter genes (Abcc2, Abcb11, and Abcg5/8), resulting in transcriptional suppression and subsequent cholestasis. Thus, hepatic macrophages, IL-1β, or NF-κB may be targets for restoring bile and sterol transport to treat PNAC. The authors previously developed a mouse model of parenteral nutrition-associated cholestasis (PNAC) that is dependent on parenteral phytosterols and intestinal injury with DSS. Here they refine the model and show that PNAC pathology is dependent on recruitment of hepatic macrophages and IL-1 signaling. |
| تدمد: | 2041-1723 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::11d09fb280bddfabd3dbb031826b8f56 https://pubmed.ncbi.nlm.nih.gov/29643332 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....11d09fb280bddfabd3dbb031826b8f56 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20411723 |
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