Patients with inflammatory diseases involving peripheral organs or tissues commonly experience altered brain function giving rise to symptoms that adversely affect their quality of life (QOL) (D’Mello and Swain, 2014). How peripheral inflammation leads to remote changes in brain function remains unclear and, as a result, there are limited therapeutic options available clinically to address this issue. A number of general pathways have been described that link systemic inflammation to changes occurring in the brain, which in turn give rise to altered behavior (Dantzer et al., 2014).

These pathways traditionally have included signaling via neural pathways (mainly vagal nerve afferents) and immune signaling (mainly via circulating cytokines, which either enter the brain directly or activate cerebral endothelium; Capuron and Miller, 2011). Recently, we described a novel peripheral signaling pathway occurring in the setting of liver inflammation, which involves increased peripheral TNF-α production driving increased microglial…