Activated microglia stimulate transcriptional changes in primary oligodendrocytes via IL-1β

No therapy currently exists to repair demyelinated lesions in multiple sclerosis. However, the use of IgM antibodies may provide a valuable therapeutic avenue for evoking such repair. Unfortunately, the mechanism of immunoglobulin action in CNS repair is currently unknown but may depend upon complex interactions between multiple cell types rather than upon direct activation of a single cell type. Using rat mixed glial cultures containing oligodendrocytes, microglia, and astrocytes, we found that the Fc portion of human IgM shifts microglia to an activated phenotype, reduces glial proliferation, upregulates a variety of immediate early genes, including JunB, Egr-1, and c-Fos, and stimulates microglial production and release of IL-1β. Microglia-derived IL-1β consequently triggers transcriptional upregulation of immediate early genes such as c-Jun, Egr-1, and c-Fos in the mixed glial cultures, and stimulates the upregulation of late response genes such as lipocalin in purified oligodendrocytes. Treatment with an IL-1β receptor antagonist abrogates the effects of Fcμ on glial proliferation and prevents the upregulation of lipocalin in response to Fcμ, but does not prevent Fcμ-mediated upregulation of IL-1β, suggesting that IL-1β mediates at least some of the downstream effects of Fcμ in mixed glial cultures. We hypothesize that Fcμ-stimulated IL-1β-induced upregulation of immediate early and late response genes in oligodendrocytes may promote CNS repair.