Title: HIF-1α-induced xenobiotic transporters promote Th17 responses in Crohn's disease.

Authors: Xie, Anyan; Robles, René J; Mukherjee, Samiran; Zhang, Haohai; Feldbrügge, Linda; Csizmadia, Eva; Wu, Yan; Enjyoji, Keiichi; Moss, Alan C; Otterbein, Leo E; Quintana, Francisco J; Robson, Simon C; Longhi, Maria Serena

Published In J Autoimmun, (2018 Nov)

Abstract: In Crohn's disease, pathogenic Th17-cells express low levels of CD39 ectonucleotidase and are refractory to the immunosuppressive effects of unconjugated bilirubin (UCB), an endogenous ligand for aryl-hydrocarbon-receptor (AhR). This resistance to AhR ligation might be associated with alterations in responses to hypoxia. Limited exposure to hypoxia appears beneficial in acute tissue injury. However, in protracted inflammation, hypoxemia may paradoxically result in Th17-cell activation. We report here that in vitro exposure of Th17-cells from Crohn's disease patients to hypoxia limits responsiveness to AhR stimulation by UCB, as reflected by lower CD39 levels. Blockade of hypoxia-inducible-factor-1alpha (HIF-1α) upregulates CD39 and favors Th17-cell regulatory responses. Resistance of Th17-cells to AhR signaling results, in part, from HIF-1α-dependent induction of ATP-binding cassette (ABC) transporters: multidrug-resistance-protein-1 (MDR1) and multidrug-resistance-associated-protein-4 (MRP4). Increased ABC transporters promote efflux of suppressive AhR ligands, such as UCB, from Th17-cells. Inhibition of MDR1, MRP4 and/or HIF-1α with ritonavir (RTV) reconstitutes AhR function in Th17-cells, enhancing therapeutic effects of UCB in dextran-sulfate-sodium-induced experimental colitis. Deleterious effects of hypoxia on Th17-cells in Crohn's disease can be ameliorated either by inhibiting HIF-1α or by suppressing ABC transporters to increase UCB availability as an AhR substrate. Targeting HIF-1α-ABC transporters could provide innovative therapeutic pathways for IBD.

PubMed ID: 30098863

MeSH Terms: ATP Binding Cassette Transporter, Subfamily B/antagonists & inhibitors; ATP Binding Cassette Transporter, Subfamily B/genetics; ATP Binding Cassette Transporter, Subfamily B/immunology; Animals; Anti-Inflammatory Agents/immunology; Anti-Inflammatory Agents/pharmacology; Apyrase/genetics; Apyrase/immunology; Basic Helix-Loop-Helix Transcription Factors/genetics; Basic Helix-Loop-Helix Transcription Factors/immunology*; Bilirubin/immunology; Bilirubin/pharmacology; Cell Hypoxia; Colitis/chemically induced; Colitis/drug therapy; Colitis/genetics; Colitis/immunology*; Crohn Disease/genetics; Crohn Disease/immunology*; Crohn Disease/pathology; Dextran Sulfate/administration & dosage; Humans; Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors; Hypoxia-Inducible Factor 1, alpha Subunit/genetics; Hypoxia-Inducible Factor 1, alpha Subunit/immunology*; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Mice, Knockout; Mucous Membrane/immunology; Mucous Membrane/pathology; Multidrug Resistance-Associated Proteins/antagonists & inhibitors; Multidrug Resistance-Associated Proteins/genetics; Multidrug Resistance-Associated Proteins/immunology*; Primary Cell Culture; Protein Binding; RNA, Small Interfering/genetics; RNA, Small Interfering/immunology; Receptors, Aryl Hydrocarbon/genetics; Receptors, Aryl Hydrocarbon/immunology*; Ritonavir/pharmacology; Th17 Cells/drug effects; Th17 Cells/immunology; Th17 Cells/pathology