During systemic infections, the immune system can signal the brain and act on different neuronal circuits via soluble molecules, such as proinflammatory cytokines, that act on the cells forming the blood-brain barrier and the circumventricular organs. These activated cells release prostaglandin of the E2 type (PGE2), which is the endogenous ligand that triggers the pathways involved in the control of autonomic functions necessary to restore homeostasis and provide inhibitory feedback to innate immunity. Among these neurophysiological functions, activation of the circuits that control the plasma release of glucocorticoids is probably the most critical to the survival of the host in the presence of pathogens. This review revisits this issue and describes in depth the molecular details (including the emerging role of Toll-like receptors during inflammation) underlying the influence of circulating inflammatory molecules on the cerebral tissue, focusing on their contribution in the synthesis and action PGE2 in the brain. We also provide an innovative view supporting the concept of “fast and delayed response” involving the same ligands but different groups of cells, signal transduction pathways, and target genes.
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