Fig. 1.

The interface of the immune and central nervous systems. Peripheral immune cells and signals reach the CNS via two primary routes: the neural pathway and the humoral pathway. (1) In the neural pathway, peripheral cytokines activate primary afferent nerves, including the vagus nerve, which terminates in the nucleus of the solitary tract (NTS) in the medulla oblongata. Second order neurons project to brainstem, hypothalamic and forebrain nuclei involved in behavioral stress response. (2) In the humoral pathway, cytokine signals cross the blood–brain barrier by transport, diffusion, or trafficking of immune cells. Cytokines in the peripheral circulation cross via cytokine transporters (a) or by activation of cytokine receptors on endothelial cells of the brain vasculature (b), leading to the production of prostaglandins E2 (PGE2), lipophilic molecules that can easily diffuse throughout the brain. Chronic social stress can also promote the recruitment of peripherally derived macrophages into the brain parenchyma of reward regions including the amygdala and prefrontal cortex (c). Cytokines produced locally by macrophage-like cells in the circumventricular organs and choroid plexus cross the BBB by volume diffusion (d). Once within the CNS, peripheral signals activate microglia that in turn produce pro-inflammatory cytokines.