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

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.

New Insights Into Intestinal Failure–Associated Liver Disease in Children

“…Deletion of macrophages, pharmacological antagonism of IL‐1β signaling (Anakinra), or genetic deficiency of C‐C chemokine receptor type 2, caspase‐1/caspase‐11, or IL‐1 receptor, prevented cholestasis in this model, suggesting several potential novel targets for therapeutic intervention in IFALD. ( 31 ) Similar hepatic transcriptional profiles of cytokines and bile and sterol transport proteins were reported in children with IFALD, ( 25 ) validating this mouse model.…”

Proteome Characteristics of Liver Tissue from Patients with Parenteral Nutrition-Associated Liver Disease

“…Inflammation triggered by macrophages induced obesity related insulin resistance [62]. Consistent with these results, previous studies had indicated that LPSmediated macrophages and IL-1β production or LPS-activated Kupffer cell through TLR4 might be early events in the pathogenesis of PNALD [63,64].…”

Prediction, identification and progression of histopathological liver disease activity in children with intestinal failure

“…We defined the active IFALD stage as the presence of histological cholestasis and/or inflammation based on the current understanding of the IFALD pathogenesis, according to which hepatic macrophage activation and increased proinflammatory cytokine production down-regulates canalicular bile transporters via their upstream nuclear receptor regulators leading to development of cholestasis (8,37,38). At diagnosis, 70% of the patients with active IFALD exhibited both cholestasis and portal inflammation, the degrees of which were positively correlated, supporting a synergistic pathophysiological connection between the two pathologies.…”