Neural and humoral pathways of communication from the immune system to the brain: parallel or convergent?

The first studies carried out on the mechanisms by which peripheral immune stimuli signal the brain to induce fever, activation of the hypothalamic-pituitary-adrenal axis and sickness behavior emphasized the importance of fenestrated parts of the blood-brain barrier known as circumventricular organs for allowing blood-borne proinflammatory cytokines to act on brain functions. The discovery in the mid-1990s that subdiaphragmatic section of the vagus nerves attenuates the brain effects of systemic cytokines, together with the demonstration of an inducible brain cytokine compartment shifted the attention from circumventricular organs to neural pathways in the transmission of the immune message to the brain. Since then, neuroanatomical studies have confirmed the existence of a fast route of communication from the immune system to the brain via the vagus nerves. This neural pathway is complemented by a humoral pathway that involves cytokines produced at the level of the circumventricular organs and the choroid plexus and at the origin of a second wave of cytokines produced in the brain parenchyma. Depending on their source, these locally produced cytokines can either activate neurons that project to specific brain areas or diffuse by volume transmission into the brain parenchyma to reach their targets. Activation of neurons by cytokines can be direct or indirect, via prostaglandins. The way the neural pathway of transmission interacts with the humoral pathway remains to be elucidated.