Early in the field of study of neural-immune interactions there was significant doubt that the peripheral immune system could signal the brain. The assumption was that large molecules such as cytokines (15–20-kD proteins) could not cross the bloodbrain barrier (BBB, 1 an anatomical and functional separation between brain parenchyma and peripheral tissues consisting of the vascular endothelium, basement membrane, neuroglial membrane, and glial perivascular feet, see Fig. 1). It was initially thought that cytokines could not easily enter the central nervous system (CNS) to affect their target sites. However, recent work has demonstrated several routes by which peripheral cytokines can either directly cross the BBB or indirectly signal the brain through other informational substances. There are three known routes by which peripheral cytokines can exert their effects on the brain:(a) peripheral tissues, which are innervated by the peripheral and autonomic nervous systems, can send direct signals to the brain via peripheral nerves;(b) brain vasculature can convey signals through secondary messengers, such as nitric oxide (NO) or prostanoids, produced in response to cytokines; and (c) cytokines can directly act at the level of the brain parenchyma after crossing the BBB or after entering brain areas that lack a BBB. Cytokine action at these sites, which are not mutually exclusive, may depend on the location and route of exposure to inflammatory stimuli and the disease state of the organism. This Perspective considers recent advances in our understanding of cytokine action at these sites.

Peripheral tissues, including immune organs, are innervated by the autonomic and peripheral nervous system. Peripheral autonomic nerves can send an immune signal to the brain. It has been shown that subdiaphragmatic, but not hepatic vagotomy, blocks intraperitoneal IL-1ß–induced hypothalamic norepinephrine depletion and attenuates intraperitoneal IL-1ß–induced increases in serum corticosterone (1). Subdiaphragmatic vagal transection attenuates the acquisition and facili-