Immunomodulatory effects of bilirubin are mediated through aryl hydrocarbon receptor, O2 and purinergic pathways

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Abstract Inflammatory bowel disease (IBD) may develop as a consequence of imbalanced immune system responses to altered gut microbiota, in genetically predisposed individuals, some of whom have defined mutations in immune response genes. New approaches are important, as IBD is a serious and common illness, which often becomes refractory to conventional immunosuppression. Chronic illness is associated with substantial morbidity, cancer risk and early death. Curiously, jaundiced patients may have spontaneous remissions from immunologic diseases, including IBD. Also, people with Gilbert's disease are less likely to develop IBD and bile pigments have been shown to induce tolerance to islet allografts and ameliorate experimental colitis. Biliverdin- bilirubin, end products of heme catabolism by heme oxygenase-1 (HO-1) have substantive immunomodulatory effects linked to the boosting of regulatory FoxP3+ T-cells (Tregs) in vitro. These effects may be impacted by expression of the multidrug resistance protein 1 (MDR1); an ATP-binding cassette transporter that pumps xenobiotics and host endogenous mediators, e.g. unconjugated bilirubin (UCB), out of cells. Bilirubin is known to interact with the aryl hydrocarbon receptor (AhR), a receptor more typically involved in responses to xenobiotics and toxins. Both the AhR and the hypoxia-inducible-factor-1-alpha (HIF-1α) closely modulate expression of CD39, an ectonucleotidase expressed by the vasculature and immune cells and critically responsible for generation of immune suppressive adenosine. We provide preliminary evidence that expression of AhR is impaired in Th17 cells from IBD patients. These Th17 cells are also defective at upregulating CD39 upon exposure of UCB in vitro. We also note that Th17 cells from IBD patients, substantively upregulate HIF-1α, which in turn further competitively inhibits AhR- mediated boosts to CD39.We propose that lipid soluble UCB induces tolerance via Treg and `suppressor' Th17 cells in IBD, through engagement of pathways involving AhR/HIF-1α and with purinergic signaling being the effector pathway. Our aims study the impact of UCB upon the Treg-Th17 cell immune axis, as modulated by the AhR, HIF-1α and the CD39-dependent pathways in murine models of experimental colitis. We dissect out how UCB impacts colitic disease phenotype and immune responses. Finally we will determine whether interventions aimed to boost UCB either by interfering with HIF-1α, boosting CD39 ectonucleotidase activity (e.g. apyrase), inhibiting bilirubin conjugation by UDP-glucuronosyltransferase (e.g. indinavir), or modulating MDR1 expression (e.g. ritonavir) can provide beneficial effects with limited toxicity. These approaches will be tested in experimental colitis in vivo and in vitro experimental systems using cells from IBD patients. In addition to providing unique connections between bilirubin, other environmental signals, O2-mediated stress and purinergic signaling, our studies will contribute to a better understanding of IBD and will also illuminate potential therapeutic approaches to curb inflammation and halt disease progression.