Macrophage Activation in CNS Remyelination

Remyelination in response to previous demyelination can occur spontaneously and is a unique regenerative response in the adult mammalian CNS. In order to understand why it fails under certain conditions such as chronic multiple sclerosis, a series of studies have investigated its cellular and molecular mechanisms critically examining the working hypothesis that remyelination (a pathological process) is a recapitulation of myelination (a developmental process). One aspect has been the examination of growth factor (GF) expression during remyelination, as there is substantial literature on astrocyte- (and neuronal-) derived GFs as mediators of oligodendrocyte behaviour during myelination. Interestingly, previous studies have shown that although some of the GF expressing cells are reactive astrocytes by far the greater proportion of GF expressing cells are macrophages. In fact, we were able to demonstrate that depleting peripheral macrophages at early stages after inducing a CNS lesion has a significant influence on the process, impairing remyelination.Using experimental models of demyelination/remyelination of rodent white matter together with transgenic and viral vector techniques for gene manipulation the project will address the following hypotheses: 1) The important early activation and recruitment of macrophages driving remyelination is in part driven by astrocyte-derived factors, 2) macrophages are a source of factors involved in activating astrocytes and hence contribute to a mutually-regulating crosstalk between themselves and astrocytes, and 3) there is an important interaction between macrophages and oligodendrocyte in the early molecular and cellular events of remyelination.