Figure 1.

Periphery-to-brain communication pathways. The periphery can communicate to the brain via neural and humoral routes. Peripheral organs project signals to varied cerebral regions via the vagus nerve (the neural route). Additionally, different humoral routes are used by the periphery to communicate to the brain: (1) Circulating immune mediators access the brain via the circumventricular organs (CVOs); (2) Peripheral immune cells cytokines and metabolites interact with their transporters on cerebral endothelial cells and choroid plexus epithelium (CPE) cells and subsequently enter to the brain; (3) Periphery-to-brain communication can occur via cell-mediated interactions between peripheral signals and brain cells which in turn lead to microglial activation and neuroinflammation. (4) Peripheral immune mediators activate choroid plexus epithelial cells and induces the release of extracellular vesicles (EVs). EVs enter the brain and can be engulfed by microglia to induce pro-inflammatory response. BBB, blood-brain barrier; CPE, choroid plexus epithelium; CVOs, circumventricular organs; CSF, cerebrospinal fluid; EVs, extracellular vesicles.