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(reg) 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 BDL 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 IL-6 production, and subsequent signalling via circulating IL-6 acting at the level of the cerebral endothelium.