Inflammation in the central nervous system is often accompanied by complement activation and the complement system has been implicated in diverse disorders such as Alzheimer's disease, amyotrophic lateral sclerosis and multiple sclerosis. We have utilized the cuprizone model of demyelination-remyelination and here show that complement is a negative factor during demyelination, however lack of an intact complement system significantly delays remyelination. In addition, there is decreased expression of the protective Crry protein, suggesting increased susceptiblity to complement activation. In support of this idea, CNS-specific soluble Crry protein completely inhibits demyelination. These results indicate that complement is active even in CNS diseases without antibody involvement (as is the case in the cuprizone model). In order to further delineate the role of complement in neuroinflammation we propose to test the following hypotheses: (1) The production of anaphylatoxin proteins plays a key role in demyelination, yet are also important for remyelination. Both C3a and C5a are produced during complement activation, yet it is very difficult to dissect the roles of these proteins, either alone or in combination. We have generated novel adenoviral constructs and we have mice with genetic deletions in the receptors for these proteins that we can use to test our hypothesis. (2) Loss of Crry expression creates an environment in the corpus callosum that facilitates complement activation. Our preliminary data have shown significant loss of Crry protein in cuprizone-treated mice and CNS production of soluble Crry protein prevents demyelination. These data show that primary demyelination can be prevented, but the effect on remyelination is yet unknown. We will use adenovirally delivered soluble Crry protein to test the ability of the protein to alter local demyelination and remyelination in this system. Our studies will begin to uncover how different complement proteins interact in the CNS to mediate diverse effector functions. This information will be critical for understanding how and when complement might be a candidate therapeutic target in CNS disease.
| Fraczek, Laura A; Martin, Carol B; Martin, Brian K (2011) c-Jun and c-Fos regulate the complement factor H promoter in murine astrocytes. Mol Immunol 49:201-10 |
| Ingersoll, Sarah A; Martin, Carol B; Barnum, Scott R et al. (2010) CNS-specific expression of C3a and C5a exacerbate demyelination severity in the cuprizone model. Mol Immunol 48:219-30 |
