title: Targeting the CD80/CD86 costimulatory pathway with CTLA4-Ig directs microglia toward a repair phenotype and promotes axonal outgrowth.
abstract: Among the costimulatory factors widely studied in the immune system is the CD28/cytotoxic T-lymphocyte antigen-4 (CTLA4)-CD80/CD86 pathway, which critically controls the nature and duration of the T-cell response. In the brain, up-regulated expression of CD80/CD86 during inflammation has consistently been reported in microglia. However, the role of CD80/CD86 molecules has mainly been studied in a context of microglia-T cell interactions in pathological conditions, while the function of CD80/CD86 in the regulation of intrinsic brain cells remains largely unknown. In this study, we used a transgenic pig line in which neurons express releasable CTLA4-Ig, a synthetic molecule mimicking CTLA4 and binding to CD80/CD86. The effects of CTLA4-Ig on brain cells were analyzed after intracerebral transplantation of CTLA4-Ig-expressing neurons or wild-type neurons as control. This model provided in vivo evidence that CTLA4-Ig stimulated axonal outgrowth, in correlation with a shift of the nearby microglia from a compact to a ramified morphology. In a culture system, we found that the CTLA4-Ig-induced morphological change of microglia was mediated through CD86, but not CD80. This was accompanied by microglial up-regulated expression of the anti-inflammatory molecule Arginase 1 and the neurotrophic factor BDNF, in an astrocyte-dependent manner through the purinergic P2Y1 receptor pathway. Our study identifies for the first time CD86 as a key player in the modulation of microglia phenotype and suggests that CTLA4-Ig-derived compounds might represent new tools to manipulate CNS microglia.
authors.affiliation: INSERM UMR 1064, ITUN, CHU Nantes, University of Nantes, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Louveau
authors.affiliation: INSERM UMR 1064, ITUN, CHU Nantes, University of Nantes, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Nerrière-Daguin
authors.affiliation: INSERM UMR 1064, ITUN, CHU Nantes, University of Nantes, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Vanhove
authors.affiliation: INSERM UMR 1064, ITUN, CHU Nantes, University of Nantes, France.|INSERM UMR 913, IMAD, University of Nantes, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Naveilhan
authors.affiliation: INSERM UMR 913, IMAD, University of Nantes, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Neunlist
authors.affiliation: INSERM UMR 1064, ITUN, CHU Nantes, University of Nantes, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Nicot
authors.affiliation: INSERM UMR 1064, ITUN, CHU Nantes, University of Nantes, France.|INSERM UMR 913, IMAD, University of Nantes, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Boudin
mesh_terms: D000069594:Abatacept / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D001253:Astrocytes / Q000166:cytology / Q000502:physiology; D001369:Axons / Q000502:physiology*; D018122:B7-1 Antigen / Q000378:metabolism*; D051940:B7-2 Antigen / Q000378:metabolism*; D016380:Brain Tissue Transplantation; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D049108:Cell Enlargement; D002478:Cells, Cultured; D018920:Coculture Techniques; D003342:Corpus Striatum / Q000166:cytology / Q000502:physiology / Q000601:surgery; D006801:Humans; D008297:Male; D017628:Microglia / Q000166:cytology / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D013552:Swine
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; D019208:Brain-Derived Neurotrophic Factor; D012333:RNA, Messenger; D000069594:Abatacept
keywords: arginase 1; brain-derived neurotrophic factor; costimulatory molecules; inflammation; neuroprotection