Fig. 2
From: The role of peripheral inflammatory insults in Alzheimer’s disease: a review and research roadmap
Peripheral inflammation affects brain function via the neuro-immune axis. Levels of inflammatory proteins increase in the blood after an inflammatory insult. Circulating inflammatory proteins can activate endothelial cells, which then upregulate cellular adhesion molecules, such as ICAM1 and VCAM1. Cellular adhesion molecules tether myeloid cells, leading to further endothelial activation and vascular inflammation. As part of this process endothelial cells activate pro-inflammatory transcription factors, causing an increased expression of pro-inflammatory factors in the brain. Circulating inflammatory proteins in blood (e.g., TNF-ɑ) can cause breakdown in blood–brain barrier tight junctions, allowing for increased flow of blood proteins into the brain parenchyma and CSF. Inflammatory proteins in blood can also be transported into the brain via receptor-mediated transcytosis, and with increasing age, non-specific caveolar transcytosis. Outside the cerebral microvessel, activation of perivascular macrophages can further enhance blood–brain barrier permeability. Comprised of fenestrated capillaries, circumventricular organs (listed in red text) are gaps within the blood–brain barrier that allow for direct communication between molecules circulating in the blood, including cytokines, and target cells within the brain. In the context of peripheral inflammation, the vagus nerve sends inflammatory signals from the gut, liver, lungs, and other organs to the brain. The solitary nucleus relays these peripherally derived inflammatory signals to the hypothalamus, thalamus, and other brain regions in a manner which can promote glial expression of inflammatory proteins and receptors. Abbreviations: AP, area postrema; ICAM1, intercellular adhesion molecule 1; IL-1β, interleukin 1 beta; IL1R1, interleukin 1 receptor type 1; IL-6, interleukin 6; ME, median eminence; NLP, neural lobe of the pituitary gland; OVLT, organum vasculosum of the lamina terminalis; PI, pineal gland; SCO, subcommissural organ; SFO, subfornical organ; TNF-ɑ, tumor necrosis factor alpha; TNFR, tumor necrosis factor receptor; VCAM1, vascular cell adhesion molecule 1