Complement anaphylatoxin function and signaling in the CNS (89.48)

Abstract

Abstract Demyelination of the CNS in autoimmune diseases is known to involve several immune effector mechanisms, including complement. The brain is considered an immunoprivileged site; however, complement proteins are produced locally by glial cells. We are investigating the roles of C3a and C5a on glial cell activation and their overall role in demyelination and remyelination pathology. Using the cuprizone model to induce demyelination, we found that transgenic mice expressing C3a or C5a in the CNS had exacerbated demyelination and slightly delayed remyelination in the corpus callosum compared to wild type mice. C3a and C5a transgenics had increased cellularity in the corpus callosum. Using immunofluorescence, it was shown that microglia and astrocyte levels were increased in the brains of transgenic mice during peak demyelination. To study the role of anaphylatoxins on individual glial subsets, we created novel adenoviral vectors to express murine C3a or C5a. ERK1/2, were phosphorylated when BV-2 microglia were stimulated with C5a, but not C3a. JNK and ERK1/2 were phosphorylated in primary astrocytes treated with C3a or C5a. Additionally, C5a was able to induce chemtoaxis in J774 macrophages; however, we did not see significant migration of astrocytes or BV-2 microglia in vitro. Overall, our findings show that anaphylatoxin production in the brain plays a negative role during demyelination, most likely due to an increase in inflammatory cells in demyelinated areas of the brain.