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C3-dependent mechanism of microglial priming relevant to multiple sclerosis.

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, which were 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.

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  • Authors

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    Source

    MeSH

    Animals
    Cell Shape
    Complement C3
    Complement C3b
    Complement Pathway, Alternative
    Cross-Priming
    Encephalomyelitis, Autoimmune, Experimental
    Humans
    Inflammation
    Inflammation Mediators
    Lipopolysaccharides
    Mice
    Mice, Inbred C57BL
    Microglia
    Models, Immunological
    Multiple Sclerosis
    Receptors, Complement
    Spinal Cord
    Up-Regulation

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    22219359