title: Complement Factor H Inhibits CD47-Mediated Resolution of Inflammation.
abstract: Variants of the CFH gene, encoding complement factor H (CFH), show strong association with age-related macular degeneration (AMD), a major cause of blindness. Here, we used murine models of AMD to examine the contribution of CFH to disease etiology. Cfh deletion protected the mice from the pathogenic subretinal accumulation of mononuclear phagocytes (MP) that characterize AMD and showed accelerated resolution of inflammation. MP persistence arose secondary to binding of CFH to CD11b, which obstructed the homeostatic elimination of MPs from the subretinal space mediated by thrombospsondin-1 (TSP-1) activation of CD47. The AMD-associated CFH(H402) variant markedly increased this inhibitory effect on microglial cells, supporting a causal link to disease etiology. This mechanism is not restricted to the eye, as similar results were observed in a model of acute sterile peritonitis. Pharmacological activation of CD47 accelerated resolution of both subretinal and peritoneal inflammation, with implications for the treatment of chronic inflammatory disease.
authors.affiliation: Institut de la Vision, 17 rue Moreau, Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, 75012 Paris, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Calippe
authors.affiliation: Institut de la Vision, 17 rue Moreau, Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, 75012 Paris, France.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Augustin
authors.affiliation: Institut de la Vision, 17 rue Moreau, Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, 75012 Paris, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Beguier
authors.affiliation: Institut de la Vision, 17 rue Moreau, Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, 75012 Paris, France.
authors.forename: Hugo
authors.initials: H
authors.lastname: Charles-Messance
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR-S 1166, Faculté de médecine Pitié-Salpétrière, 91 Boulevard de l'hôpital, 75013 Paris, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Poupel
authors.affiliation: Institut de la Vision, 17 rue Moreau, Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, 75012 Paris, France.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Conart
authors.affiliation: Institut de la Vision, 17 rue Moreau, Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, 75012 Paris, France.
authors.forename: Shulong J
authors.initials: SJ
authors.lastname: Hu
authors.affiliation: Institut de la Vision, 17 rue Moreau, Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, 75012 Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lavalette
authors.affiliation: Institut de la Vision, 17 rue Moreau, Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, 75012 Paris, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Fauvet
authors.affiliation: Université Paris Descartes, Unité Mixte de Recherche en Santé 872, Centre de Recherche des Cordeliers, 75006 Paris, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Rayes
authors.affiliation: Institut de la Vision, 17 rue Moreau, Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, 75012 Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Levy
authors.affiliation: Institut de la Vision, 17 rue Moreau, Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, 75012 Paris, France.
authors.forename: William
authors.initials: W
authors.lastname: Raoul
authors.affiliation: Unité Cytokines & Inflammation, Département Infection et Epidémiologie, Institut Pasteur, 75015 Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Fitting
authors.affiliation: Laboratoire des Biomolécules, UMR 7203 and FR 2769, Sorbonne Universités, Université Pierre et Marie Curie, Paris, France; Centre National de la Recherche Scientifique, UMR 7203 Paris, France; Département de Chimie, École Normale Supérieure, 75005 Paris, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Denèfle
authors.affiliation: Centre for Complement and Inflammation Research, Department of Medicine, Imperial College, London W12 0NN, UK.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Pickering
authors.affiliation: Institute of Infection and Immunity, Cardiff University, Cardiff CF10 3XQ, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Harris
authors.affiliation: LFB Biotechnologies, 59000 Lille, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Jorieux
authors.affiliation: Department of Medicine, Centers for Aging and Geriatric Research Education and Clinical Center, Durham Veteran Affairs Medical Center, Duke University, Durham, NC 27710, USA.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Sullivan
authors.affiliation: Institut de la Vision, 17 rue Moreau, Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, 75012 Paris, France.
authors.forename: José-Alain
authors.initials: JA
authors.lastname: Sahel
authors.affiliation: Laboratoire des Biomolécules, UMR 7203 and FR 2769, Sorbonne Universités, Université Pierre et Marie Curie, Paris, France; Centre National de la Recherche Scientifique, UMR 7203 Paris, France; Département de Chimie, École Normale Supérieure, 75005 Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Karoyan
authors.affiliation: Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Montreal, QC H3T 1J4, Canada.
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Sapieha
authors.affiliation: Institut de la Vision, 17 rue Moreau, Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, 75012 Paris, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Guillonneau
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR-S 1166, Faculté de médecine Pitié-Salpétrière, 91 Boulevard de l'hôpital, 75013 Paris, France.
authors.forename: Emmanuel L
authors.initials: EL
authors.lastname: Gautier
authors.affiliation: Institut de la Vision, 17 rue Moreau, Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, 75012 Paris, France. Electronic address: florian.sennlaub@inserm.fr.
authors.forename: Florian
authors.initials: F
authors.lastname: Sennlaub
mesh_terms: D000818:Animals; D051928:CD47 Antigen / Q000276:immunology*; D017242:Complement Factor H / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000276:immunology*; D008268:Macular Degeneration / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D010538:Peritonitis / Q000235:genetics / Q000276:immunology; D020641:Polymorphism, Single Nucleotide
chemical_list: D051928:CD47 Antigen; D017242:Complement Factor H