CNS-specific expression of C3a and C5a exacerbate demyelination severity in the cuprizone model.
Demyelination in the central nervous system (CNS) is known to involve several immune effector mechanisms, including complement proteins. Local production of complement by glial 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 mice expressing C3a or C5a under the control of the glial 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 glial 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.
Ingersoll
Sarah A
SA
Interdisciplinary Graduate Program in Immunology, University of Iowa, 357 Medical Research Center, Iowa City, IA 52242, USA. sarah-ingersoll@uiowa.edu
Martin
Carol B
CB
Barnum
Scott R
SR
Martin
Brian K
BK
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D015926:Complement C3a / Q000276:immunology* / Q000378:metabolism; D015936:Complement C5a / Q000276:immunology* / Q000378:metabolism; D003471:Cuprizone / Q000633:toxicity; D003711:Demyelinating Diseases / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008996:Monoamine Oxidase Inhibitors / Q000633:toxicity; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000276:immunology*; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000276:immunology
D008996:Monoamine Oxidase Inhibitors; D003471:Cuprizone; D015926:Complement C3a; D015936:Complement C5a
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