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

Background & AimsCholestatic liver diseases are commonly accompanied by debilitating symptoms, collectively termed sickness behaviours. Regulatory T cells (Tregs) can suppress inflammation; however, a role for Tregs in modulating sickness behaviours has not been evaluated.MethodsA mouse model of cholestatic liver injury due to bile duct ligation (BDL) was used to study the role of Tregs in sickness behaviour development.ResultsBDL mice developed reproducible sickness behaviours, as assessed in a social investigation paradigm, characterized by decreased social investigative behaviour and increased immobility. Depletion of peripheral Tregs in BDL mice worsened BDL-associated sickness behaviours, whereas infusion of Tregs improved these behaviours; however, liver injury severity was not altered by Treg manipulation. Hepatic IL-6 mRNA and circulating IL-6 levels were elevated in BDL vs. control mice, and were elevated further in Treg-depleted BDL mice, but were decreased after infusion of Tregs 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.ConclusionsTregs modulate sickness behaviour development in the setting of cholestatic liver injury, driven mainly through Treg inhibition of circulating monocyte and hepatic IL-6 production, and subsequent signalling via circulating IL-6 acting at the level of the cerebral endothelium.