process formation, and increasing death39. In EAE, ultrastructural analysis demonstrated infiltrating monocytes appearing to pull myelin off the axon170; together with the known requirement of monocytes to initiate disease in EAE171, this suggests an important interaction between monocytes and myelin processes in inducing demyelination. Accordingly, macrophage depletion via small molecule inhibition of the pro-survival receptor CSF1R is sufficient to reduce OL loss and demyelination in the cuprizone model, and administration of the ligand CSF1 is sufficient to cause demyelination172. Microglia are in close communication with astrocytes to drive demyelination, as seen in EAE13, through secretion of pro-inflammatory cytokines, complement signaling47, and semaphorin and ephrin signaling173. Although direct mechanisms by which microglia interact with mature OLs to regulate their responses are not clear, a study in zebrafish showed that microglia engulf myelin sheaths to regulate sheath number in developmental myelination174. In addition, microglia in the presence of astrocytes induce OL death through TNFα after exposure to the pro-inflammatory stimuli lipopolysaccharide (LPS)175. Astrocytes may also contribute to demyelination indirectly via induction of BBB breakdown and expression of chemokines that recruit peripheral immune cells176–180. Human OLs are however resistant to toxic effects of conditioned media from astrocytes preconditioned by immune cell supernatants, whereas
