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

Abstract

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. 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. 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. 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.