Underlying Mechanisms of Immune to Brain Communication

How the immune system initiates and maintains these adaptation depends on the locality, type and severity of the inflammatory stimulus and three principle routes of immune to brain communication have been described: (1) a neuronal route, via the vagus nerve; (2) a humoral route, via pro-inflammatory mediators in the circulation that interact with the intact cerebral vasculature and (3) a direct route via circum- ventricular organs (CVOs), which are structures in the brain that are characterized by their extensive vasculature, fenestrated capillaries and lack of a normal blood brain barrier (BBB) [18]. Evidence for neuronal signalling comes from studies on the vagus nerve, which expresses interleukin (IL)-1p, tumor necrosis factor a (TNFa) and prostaglandin receptors on the afferent fibers allowing detection of local inflammation [19-21]. While vagal signalling contributes to social withdrawal and fever in rodents, other behavioural adaptations such as anhedonia, anxiety, mood and memory do not only depend on neuronal signalling and involve a humoral route via proinflammatory mediators [22, 23]. These mediators that act on pathogen recognition receptors (PRRs) and cytokine receptors expressed on endothelial cells and perivascular macrophages at the BBB, resulting in de novo cytokine and PGE2 production by microglia [24-26]. The most widely studied cytokines produced in the CNS following peripheral LPS challenge are IL-1p and TNFa, which influence a number of behavioural changes and associated changes to microglia and neuronal function [22, 27]. The cell type responsible for the de novo transcription of cytokines remains unknown, although immunohistochemical analysis suggest that endothelial cells are the predominant cells in young, healthy rodent brains that produce IL-1p protein [28]. The behavioural and neuroinflammatory changes are not solely dependent on IL-1p and TNFa; IL-10 deficient mice show an increased and prolonged behavioural and neuroinflammatory response to systemic LPS administration, suggesting that regulation depends on a balance between pro- and antiinflammatory mediators [29]. Furthermore, abrogation of peripheral cytokines

(IL-ip, IL-6 and TNFa) either separately or simultaneously with blocking antibodies has been shown to only partially attenuate behavioural changes and do not affect central cytokine production in response to LPS [22, 30]. This suggests that although they are not mutually exclusive; LPS can directly activate brain endothelial cells or induce other factors that promote de novo cytokine synthesis in the brain. These factors include the enzymes COX-i and COX-2 that catalyse prostaglandin production [31, 32] and indoleamine 2,3-dioxygenase (IDO), an enzyme that degrades tryptophan and can be induced by INFy and TNFa. Both enzymes are expressed in microglia and endothelial cells and pharmacological inhibition has been shown to abrogate depressive like behaviour in acute and chronic inflammation [33, 34]. Astrocytes may also contribute to immune to brain communication, either by producing pro-inflammatory mediators or by modulating the BBB, but these pathways and underlying mechanisms are beyond the scope of this chapter.

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