Fig. 2

Pathways involved in the immune-to-brain communication. Three pathways participate in the immune-to-brain communication: humoral, neural and cellular (leukocyte) routes. Tissue-resident macrophages get activated by pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). Both PAMPs (infections) and DAMPs (sterile injury) engage inflammatory signalling pathways, such as nuclear factor-κB (NF-κB). The pro-inflammatory cytokines in turn are promptly secreted and enter the bloodstream. The plasma cytokines can reach the brain through various mechanisms, including the i) active transport by crossing the brain-blood barrier (BBB) through leaky areas in the circumventricular organs (humoral route); or ii) through the activation of afferent neural pathways (e.g., the vagus nerve). The leukocytic route is another mechanism of immune-to-brain communication and is mediated by the migration of circulating leukocytes to the brain borders. Leukocytes are present in small numbers in brain circumventricular organs and choroid plexus. Under healthy conditions, these peripheral immune cells support neuronal function and scan the brain for pathogens or tissue damage