CNS-specific expression of C3a and C5a exacerbate demyelination severity in the cuprizone model

Demyelination in the central nervous system (CNS) is know n to involve several immune effector mechanisms including complement proteins Local production of complement by ghat cells in the brain can be both harmful and protective To investigate the roles of C3a and C5a in demyelination and remyelination pathology we utilized the cuprizone model Transgenic mite expressing C3a or C5a under the control of the ghat fibrillary acidic protein (GFAP) promoter had exacerbated demyelination and slightly delayed remyelination in the corpus callosum compared to WT mice C3a and C5a transgenic mice had increased cellularity in the corpus callosum due to increase activation and/or migration of microglia Oligodendrocytes migrated to the corpus callosum in higher numbers during early remyelination events in C3a and C5a transgenic mice thus enabling these mice to remyelinate as effectively as WT mice by the end of the 10 week study To determine the effects of C3a and/or C5a on individual glial subsets we created murine recombinant C3a and C5a proteins When microglia and mixed ghat cultures were stimulated with C3a and/or C5a we observed an increase in the production of proinflammatory cytokines and chemokines In contrast astrocytes had decreased cytokine and chemokine production in the presence of C3a and/or C5a We also found that the MAPK pathway proteins JNK and ERK1/2 were activated in glia upon stimulation with C3a and C5a Overall our findings show that although C3a and C5a production in the brain play a negative role during demyelination these proteins may aid in remyelination (C) 2010 Elsevier Ltd All rights reserved