C3-dependent mechanism of microglial priming relevant to multiple sclerosis

Valeria Ramaglia, Timothy R. Hughes, Rossen M. Donev, Marieta M. Ruseva, Xiaobo Wu, Inge Huitinga, Frank Baas, James W. Neal, B. Paul Morgan

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78 Scopus citations

Abstract

Microglial priming predisposes the brain to neurodegeneration and affects disease progression. The signal to switch from the quiescent to the primed state is unknown. We show that deleting the C3 convertase regulator complement receptor 1-related protein y (Crry) induces microglial priming.Mice that were double-knockout for Crry and either C3 or factor B did not show priming, demonstrating dependence on alternative pathway activation. Colocalization of C3b/iC3b and CR3 implicated the CR3/iC3b interaction in priming. Systemic lipopolysaccharide challenge overactivated primed microglia with florid expression of proinflammatory molecules, whichwere blocked by complement inhibition. Relevance for neurodegenerative disease is exemplified by human multiple sclerosis (MS) and by experimental autoimmune encephalomyelitis (EAE), a model of MS. In human MS, microglial priming was evident in perilesional white matter, in close proximity to C3b/iC3b deposits. EAE was accelerated and exacerbated in Crry-deficient mice, and was dependent on C activation. In summary, C3-dependent microglial priming confers susceptibility to other challenges. Our observations are relevant to progression in MS and other neurological diseases exacerbated by acute insults.

Original languageEnglish
Pages (from-to)965-970
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number3
DOIs
StatePublished - Jan 17 2012

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    Ramaglia, V., Hughes, T. R., Donev, R. M., Ruseva, M. M., Wu, X., Huitinga, I., Baas, F., Neal, J. W., & Morgan, B. P. (2012). C3-dependent mechanism of microglial priming relevant to multiple sclerosis. Proceedings of the National Academy of Sciences of the United States of America, 109(3), 965-970. https://doi.org/10.1073/pnas.1111924109