Regulatory T cells suppress sickness behaviour development without altering liver injury in cholestatic mice

Background & Aims: Cholestatic liver diseases are commonly accompanied by debilitating symptoms, collectively termed sickness behaviours. Regulatory T cells (T-regs) can suppress inflammation; however, a role for T-regs in modulating sickness behaviours has not been evaluated. Methods:A mouse model of cholestatic liver injury due to bile duct ligation (BDL) was used to study the role of T-regs in sickness behaviour development. Results: BDL mice developed reproducible sickness behaviours, as assessed in a social investigation paradigm, characterized by decreased social investigative behaviour and increased immobility. Depletion of peripheral T-regs in BDL mice worsened BDL-associated sickness behaviours, whereas, infusion of T-regs improved these behaviours; however, liver injury severity was not altered by T-regs manipulation. Hepatic IL-6 mRNA and circulating IL-6 levels were elevated in BDL vs. control mice, and were elevated further in T-reg-depleted BDL mice, but were decreased after infusion of T-regs in BDL mice. IL-6 knock out (KO) BDL mice exhibited a marked reduction in sickness behaviours, compared to wildtype BDL mice. Furthermore, IL-6 KO BM, mice injected with rmIL-6 displayed sickness behaviours similar to wildtype BDL mice, whereas saline injection did not alter behaviour in IL-6 KO BDL mice. BDL was associated with increased hippocampal cerebral endothelial cell p-STAT3 expression, which was significantly reduced in IL-6 KO BDL mice. Conclusions: T-regs modulate sickness behaviour development in the setting of cholestatic liver injury; driven mainly through T-reg inhibition of circulating monocyte and hepatic 1L-6 production, and subsequent signalling via circulating 1L-6 acting at the level of the cerebral endothelium. (C) 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.