C3-dependent mechanism of microglial priming relevant to multiple sclerosis.
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.
Department of Infection, Immunity, and Biochemistry, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom. v.ramaglia@amc.nl
Valeria
V
Ramaglia
Timothy R
TR
Hughes
Rossen M
RM
Donev
Marieta M
MM
Ruseva
Xiaobo
X
Wu
Inge
I
Huitinga
Frank
F
Baas
James W
JW
Neal
B Paul
BP
Morgan
D000818:Animals; D048430:Cell Shape; D003176:Complement C3 / Q000276:immunology*; D003179:Complement C3b / Q000276:immunology; D003170:Complement Pathway, Alternative / Q000276:immunology; D045142:Cross-Priming / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000276:immunology* / Q000473:pathology*; D018448:Models, Immunological; D009103:Multiple Sclerosis / Q000276:immunology* / Q000473:pathology*; D011951:Receptors, Complement / Q000172:deficiency / Q000378:metabolism; D017463:Receptors, Complement 3b; D013116:Spinal Cord / Q000276:immunology / Q000473:pathology; D015854:Up-Regulation
D003176:Complement C3; C081470:Cr1l protein, mouse; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D011951:Receptors, Complement; D017463:Receptors, Complement 3b; D003179:Complement C3b