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 and Ronald J. Sokol ()
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Karim C. El Kasmi: University of Colorado School of Medicine
Padade M. Vue: University of Colorado School of Medicine
Aimee L. Anderson: University of Colorado School of Medicine
Michael W. Devereaux: University of Colorado School of Medicine
Swati Ghosh: University of Colorado School of Medicine
Natarajan Balasubramaniyan: University of Colorado School of Medicine
Sophie A. Fillon: University of Colorado School of Medicine
Carola Dahrenmoeller: University of Colorado School of Medicine
Ayed Allawzi: University of Colorado School of Medicine
Crystal Woods: University of Colorado School of Medicine
Sarah McKenna: University of Colorado School of Medicine
Clyde J. Wright: University of Colorado School of Medicine
Linda Johnson: University of Colorado School of Medicine
Angelo D’Alessandro: University of Colorado School of Medicine
Julie A. Reisz: University of Colorado School of Medicine
Eva Nozik-Grayck: University of Colorado School of Medicine
Frederick J. Suchy: University of Colorado School of Medicine
Ronald J. Sokol: University of Colorado School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03764-1

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