Macrophage-derived IL-1β/NF-κB signaling mediates parenteral nutrition-associated cholestasis

• Published in: Nature communications 2018-04, Vol.9 (1), p.1393-14, Article 1393
• Main Authors: El Kasmi, Karim C., Vue, Padade M., Anderson, Aimee L., Devereaux, Michael W., Ghosh, Swati, Balasubramaniyan, Natarajan, Fillon, Sophie A., Dahrenmoeller, Carola, Allawzi, Ayed, Woods, Crystal, McKenna, Sarah, Wright, Clyde J., Johnson, Linda, D’Alessandro, Angelo, Reisz, Julie A., Nozik-Grayck, Eva, Suchy, Frederick J., Sokol, Ronald J.
• Format: Article
• Language: English
• Subjects: 13/95; 38/77; 631/250/2504/342/1591; 64; 64/60; 692/308/3187; 692/699/1503; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 11 - genetics; ATP Binding Cassette Transporter, Subfamily B, Member 11 - immunology; ATP Binding Cassette Transporter, Subfamily G, Member 5 - genetics; ATP Binding Cassette Transporter, Subfamily G, Member 5 - immunology; Bile; Caspase; Caspase 1 - genetics; Caspase 1 - immunology; Caspase-1; Caspase-11; Caspases - genetics; Caspases - immunology; Caspases, Initiator; Catheters; CC chemokine receptors; CCR2 protein; Chemical bonds; Cholestasis; Cholestasis - etiology; Cholestasis - genetics; Cholestasis - immunology; Cholestasis - pathology; Disease Models, Animal; Enteral feeding; Enteral nutrition; Gallbladder diseases; Gene Expression Regulation; Hepatocytes - immunology; Hepatocytes - pathology; Humanities and Social Sciences; Humans; Infant, Newborn; Infants; Interleukin 1; Interleukin 1 receptors; Interleukin-1beta - genetics; Interleukin-1beta - immunology; Intestine; Lipoproteins - genetics; Lipoproteins - immunology; Liver; Liver - immunology; Liver - pathology; Liver diseases; Liver X receptors; Liver X Receptors - genetics; Liver X Receptors - immunology; Macrophages; Macrophages - immunology; Macrophages - pathology; Male; Mice; Monocyte chemoattractant protein 1; multidisciplinary; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins - genetics; Multidrug Resistance-Associated Proteins - immunology; NF-kappa B - genetics; NF-kappa B - immunology; NF-κB protein; Nutrition; Parenteral nutrition; Parenteral Nutrition - adverse effects; Pathogenesis; Pharmacology; Phytosterols; Receptors, CCR2 - deficiency; Receptors, CCR2 - genetics; Receptors, CCR2 - immunology; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - immunology; Receptors, Interleukin-1 - genetics; Receptors, Interleukin-1 - immunology; Rodents; Science; Science (multidisciplinary); Signal Transduction; Signaling; Sterols; Transcription
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-03764-1

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.