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.

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 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

  • 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 Proteins
  • NF-kappa B
  • Receptors, CCR2
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Interleukin-1
  • farnesoid X-activated receptor
  • multidrug resistance-associated protein 2
  • Casp4 protein, mouse
  • Caspases
  • Caspases, Initiator
  • Casp1 protein, mouse
  • Caspase 1