title: Decay-accelerating factor (CD55) is expressed by neurons in response to chronic but not acute autoimmune central nervous system inflammation associated with complement activation.
abstract: There is compelling evidence that a unique innate immune response in the CNS plays a critical role in host defense and clearance of toxic cell debris. Although complement has been implicated in neuronal impairment, axonal loss, and demyelination, some preliminary evidence suggests that the initial insult consequently activates surrounding cells to signal neuroprotective activities. Using two different models of experimental autoimmune encephalomyelitis, we herein demonstrate selective C1q complement activation on neuron cell bodies and axons. Interestingly, in brains with chronic but not acute experimental autoimmune encephalomyelitis, C3b opsonization of neuronal cell bodies and axons was consistently associated with robust neuronal expression of one of the most effective complement regulators, decay-accelerating factor (CD55). In contrast, levels of other complement inhibitors, complement receptor 1 (CD35), membrane cofactor protein (CD46), and CD59 were largely unaffected on neurons and reactive glial cells in both conditions. In vitro, we found that proinflammatory stimuli (cytokines and sublytic doses of complement) failed to up-regulate CD55 expression on cultured IMR32 neuronal cells. Interestingly, overexpression of GPI-anchored CD55 on IMR32 was capable of modulating raft-associated protein kinase activities without affecting MAPK activities and neuronal apoptosis. Critically, ectopic expression of decay-accelerating factor conferred strong protection of neurons against complement attack (opsonization and lysis). We conclude that increased CD55 expression by neurons may represent a key protective signaling mechanism mobilized by brain cells to withstand complement activation and to survive within an inflammatory site.
authors.affiliation: Brain Inflammation Immunity Group (BIIG), Cardiff University, Cardiff, United Kingdom. jvbe@lundbeck.com
authors.forename: Johan
authors.initials: J
authors.lastname: van Beek
authors.forename: Marjan
authors.initials: M
authors.lastname: van Meurs
authors.forename: Bert A
authors.initials: BA
authors.lastname: 't Hart
authors.forename: Herbert P M
authors.initials: HP
authors.lastname: Brok
authors.forename: Jim W
authors.initials: JW
authors.lastname: Neal
authors.forename: Alexandra
authors.initials: A
authors.lastname: Chatagner
authors.forename: Claire L
authors.initials: CL
authors.lastname: Harris
authors.forename: Nader
authors.initials: N
authors.lastname: Omidvar
authors.forename: B Paul
authors.initials: BP
authors.lastname: Morgan
authors.forename: Jon D
authors.initials: JD
authors.lastname: Laman
authors.forename: Philippe
authors.initials: P
authors.lastname: Gasque
mesh_terms: D000208:Acute Disease; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D017209:Apoptosis / Q000276:immunology; D001369:Axons / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018958:CD55 Antigens / Q000096:biosynthesis* / Q000502:physiology; D018957:CD59 Antigens / Q000096:biosynthesis; D002144:Callithrix; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology; D002908:Chronic Disease; D015941:Complement Hemolytic Activity Assay; D003171:Complement Pathway, Classical / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology*; D017261:Glycosylphosphatidylinositols / Q000502:physiology; D006801:Humans; D020014:K562 Cells; D008252:Macaca fascicularis; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D021962:Membrane Microdomains / Q000276:immunology / Q000378:metabolism; D009474:Neurons / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D009895:Opsonin Proteins / Q000378:metabolism; D017463:Receptors, Complement 3b / Q000096:biosynthesis; D015398:Signal Transduction / Q000276:immunology; D020298:U937 Cells
chemical_list: D015703:Antigens, CD; C497857:CD46 protein, human; D018958:CD55 Antigens; D018957:CD59 Antigens; D017261:Glycosylphosphatidylinositols; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins; D009895:Opsonin Proteins; D017463:Receptors, Complement 3b