Brain inflammation: the case of CGRP

The central nervous system was thought to be an immune-privileged organ: the view is changing, and it is now referred to as immune-specialized. Moreover, brain inflammation is recognized to cause not only severe neuroinflammatory diseases such as multiple sclerosis, but also to be underlying in classic neurodegenerative diseases as Parkinson's and Alzheimer's disease. The main brain immune effector cells are microglia that are considered to be general homeostatic guardians of the central nervous system. Following severe or chronic challenges microglia can produce a maladaptive response which is hypothesized to be a major cause of deleterious self-sustaining neuroinflammatory/neurodegenerative processes. Among microglia regulators, CGRP is emerging as new potent player in the intricate balance of homeostatic mechanisms. The action of the peptide in neuroinflammation has been addressed in experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis). The peptide and RCP (a receptor component) were upregulated during EAE, and the peptide was shown to exert a potent inhibition of inflammatory activation of microglia in vitro. Genetic ablation of alpha-CGRP gene worsened EAE clinical signs in mice. Moreover, the intrathecal delivery of the peptide (in mouse lumbar spinal CSF) induced amelioration of EAE clinical signs and inhibition of morphological microglia activation. Concomitantly, RCP showed cell-specific nuclear trafficking in the spinal cord glial cells. An overview of the complex cellular interactions underlying neuroinflammation triggering processes and homeostatic recovery attempts (driven, in particular, by CGRP) will be presented.