Fig. 1

Overview of routes by which peripherally produced IL-1 is able to influence IL-1 levels in the brain. An overview of the five different routes that can be used by peripherally produced IL-1α and IL-1β to access the CNS. The first route (1) is diffusion of IL-1 trough the fenestrated endothelium surrounding blood vessels in the circumventricular organs (CVOs). The rest of the brain microvasculature is surrounded by the blood-brain barrier (BBB), where diffusion is not possible due to tight junctions between cells. In these areas, IL-1 can be transported across the BBB by a saturable transport system (2), or it can activate perivascular macrophages at the brain side of blood vessels, stimulating them to produce IL-1 (3). These three routes combined are frequently described as the humoral pathway, which is able to activate microglial cells in the brain parenchyma (5). Another important system is the neuronal pathway, where peripherally produced IL-1 stimulates afferent nerves, especially the vagal nerve, causing local IL-1 production in the CNS by microglial cells (4). Increased concentrations of IL-1 in different areas of the brain are suspected to influence neurotransmitter systems (e.g., dopamine and serotonin), thereby exerting its effect on behavior and the development of fatigue