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* Brain inflammation and Immunity Group BIIG, Department of Medical Biochemistry and
Department of Histopathology, School of Medicine, Cardiff University, Cardiff, United Kingdom;
Institut National de la Santé et de la Recherche Médicale Unité 413, Federative Institute for Peptide Research 23, Faculty of Sciences, University of Rouen, Mont Saint-Aignan, France; and
Groupe de Recherche sur les Maladies Infectieuses et Inflammatoires, Infection and Inflammation Research Grouping, Departmental Hospital Centre et Molecular Genetics and Biochemistry Laboratory, Faculty of Sciences and Technology, University of la Reunion, Saint Denis, Reunion
The CNS innate immune response is a "double-edged sword" representing a fine balance between protective antipathogen responses and detrimental neurocytotoxic effects. Hence, it is important to identify the key regulatory mechanisms involved in the control of CNS innate immunity and which could be harnessed to explore novel therapeutic avenues. In analogy to the newly described neuroimmune regulatory proteins also known as "don’t eat me" signals (CD200, CD47, CD22, fractalkine, semaphorins), we herein identify the key role of complement regulator factor H (fH) in controlling neuroinflammation initiated in an acute mouse model of Ab-dependent experimental autoimmune encephalomyelitis. Mouse fH was found to be abundantly expressed by primary cultured neurons and neuronal cell lines (N1E115 and Neuro2a) at a level comparable to BV2 microglia and CLTT astrocytes. Mouse neurons expressed other complement regulators crry and low levels of CD55. In the brain, the expression of fH was localized to neuronal bodies and axons, endothelial cells, microglia but not oligodendrocytes and myelin sheaths and was dramatically reduced in inflammatory experimental autoimmune encephalomyelitis settings. When exogenous human fH was administered to disease Ab-dependent experimental autoimmune encephalomyelitis animals, there was a significant decrease in clinical score, inflammation, and demyelination, as compared with PBS-injected animals. We found that the accumulation of human fH in the brain parenchyma protected neurons from complement opsonization, axonal injury, and leukocyte infiltration. Our data argue for a key regulatory activity of fH in neuroprotection and provide novel therapeutic avenues for CNS chronic inflammatory diseases.
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1 P.G. is a Contrat d’Interface Fellow of the Institut National de la Santé et de la Recherche Médicale Unité 543 (Prof. P. Debré) and received support from the Medical Research Council (U.K.), the French Ministry of Overseas Department, and European funding (Contrat de Plan etat Region/Fonds européen de développement regional).
2 Address correspondence and reprint requests Prof. Philippe Gasque, Groupe de Recherche sur les Maladies Infectieuses et Inflammatoires, GRII, Laboratoire de Génétique et Biologie Moléculaire, LBGM, Faculté des Sciences et Technologies, 15 Avenue René Cassin, 97415, Saint Denis, Ile de la Reunion. E-mail addresses: gasquep{at}hotmail.com and gasque{at}uni-reunion.fr
3 Abbreviations used in this paper: NIReg, neuroimmune regulatory protein; DAF, decay-accelerating factor; MS, multiple sclerosis; fH, factor H; MOG, myelin oligodendrocyte glycoprotein; ADEA, Ab-dependent experimental autoimmune encephalomyelitis; EAE, experimental autoimmune encephalomyelitis; LFB/CV, Luxol fast blue/cresyl violet; TRITC, tetramethylrhodamine; DAPI, 4',6-diamidino-2-phenylindole; DAB, diaminobenzidine; NFL, neurofiilament L chain; TCS, tissue culture supernatant.
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