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

Karim C El Kasmi; Padade M Vue; Aimee L Anderson; Michael W Devereaux; Swati Ghosh; Natarajan Balasubramaniyan; Sophie A Fillon; Carola Dahrenmoeller; Ayed Allawzi; Crystal Woods; Sarah McKenna; Clyde J Wright; Linda Johnson; Angelo D'Alessandro; Julie A Reisz; Eva Nozik-Grayck; Frederick J Suchy; Ronald J Sokol

doi:10.1038/s41467-018-03764-1

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

Nat Commun. 2018 Apr 11;9(1):1393. doi: 10.1038/s41467-018-03764-1.

Authors

Karim C El Kasmi^{1

2

3}, Padade M Vue^{4

5

6}, Aimee L Anderson^{4

5}, Michael W Devereaux^{4

5}, Swati Ghosh^{4

5}, Natarajan Balasubramaniyan^{4

5}, Sophie A Fillon^{4

5}, Carola Dahrenmoeller^{4

5

7}, Ayed Allawzi⁸, Crystal Woods^{4

5}, Sarah McKenna⁹, Clyde J Wright⁹, Linda Johnson¹⁰, Angelo D'Alessandro^{8

11}, Julie A Reisz^{8

11}, Eva Nozik-Grayck⁸, Frederick J Suchy^{4

5}, Ronald J Sokol^{12

13}

Affiliations

¹ Department of Pediatrics, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, CO, 80045, USA. [email protected].
² Pediatric Liver Center, Digestive Health Institute, Children's Hospital Colorado, Aurora, CO, 80045, USA. [email protected].
³ Department of Immunology and Respiratory, Boehringer-Ingelheim Pharma GmbH &Co. KG, Birkendorferstrasse 65, 88397, Biberach an der Riss, Germany. [email protected].
⁴ Department of Pediatrics, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, CO, 80045, USA.
⁵ Pediatric Liver Center, Digestive Health Institute, Children's Hospital Colorado, Aurora, CO, 80045, USA.
⁶ Department of Pediatrics, Providence Pediatric Gastroenterology, University of Washington, Anchorage, AK, 99515, USA.
⁷ Laboratory for Gastroenterology and Hepatology (GAEN), IREC, Universite Catholique de Louvain, Belgium 1, Place de l'Université, 1348, Louvain-la-Neuve, Belgium.
⁸ Cardiovascular Pulmonary Research and Division of Pediatric Critical Care, Department of Pediatrics, University of Colorado School of Medicine, 12800 East 19th Avenue, Aurora, CO, 80045, USA.
⁹ Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, 12800 East 19th Avenue, Aurora, CO, 80045, USA.
¹⁰ Department of Pathology, University of Colorado School of Medicine, Building RC-1, North Tower, 12800 East 19th Avenue, Aurora, CO, 80045, USA.
¹¹ Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, 12801, E 17th Ave, Aurora, CO, 80045, USA.
¹² Department of Pediatrics, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, CO, 80045, USA. [email protected].
¹³ Pediatric Liver Center, Digestive Health Institute, Children's Hospital Colorado, Aurora, CO, 80045, USA. [email protected].

Abstract

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

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
Animals
Caspase 1 / genetics
Caspase 1 / immunology
Caspases / genetics
Caspases / immunology
Caspases, Initiator
Cholestasis / etiology
Cholestasis / genetics*
Cholestasis / immunology
Cholestasis / pathology
Disease Models, Animal
Gene Expression Regulation
Hepatocytes / immunology
Hepatocytes / pathology
Humans
Infant, Newborn
Interleukin-1beta / genetics*
Interleukin-1beta / immunology
Lipoproteins / genetics
Lipoproteins / immunology
Liver / immunology*
Liver / pathology
Liver X Receptors / genetics
Liver X Receptors / immunology
Macrophages / immunology*
Macrophages / pathology
Male
Mice
Multidrug Resistance-Associated Protein 2
Multidrug Resistance-Associated Proteins / genetics
Multidrug Resistance-Associated Proteins / immunology
NF-kappa B / genetics*
NF-kappa B / immunology
Parenteral Nutrition / adverse effects
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
Signal Transduction

Substances

ABCC2 protein, human
ABCG5 protein, mouse
ATP Binding Cassette Transporter, Subfamily B, Member 11
ATP Binding Cassette Transporter, Subfamily G, Member 5
Abcb11 protein, mouse
Ccr2 protein, mouse
IL1B protein, mouse
Interleukin-1beta
Lipoproteins
Liver X Receptors
Multidrug Resistance-Associated Protein 2
Multidrug Resistance-Associated Proteins
NF-kappa B
Receptors, CCR2
Receptors, Cytoplasmic and Nuclear
Receptors, Interleukin-1
farnesoid X-activated receptor
Casp4 protein, mouse
Caspases
Caspases, Initiator
Casp1 protein, mouse
Caspase 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding