title: CCR2/CCL2-mediated inflammation protects photoreceptor cells from amyloid-β-induced apoptosis.
abstract: Age-related macular degeneration is characterized by the formation of drusen containing amyloid-β (Aβ) and the degeneration of photoreceptors. To explore the largely unknown role of Aβ in the retina, we investigated the effects on photoreceptors of the oligomeric form of Aβ(1-42). Subretinal injection of the Aβ peptide induced misplaced expression of recoverin and synaptophysin in the photoreceptors, oxidative stress in their inner and outer segments, and finally apoptosis. Aβ did not induce cell death in purified photoreceptor cell cultures, but did so in retinal cell cultures, thereby suggesting that the cellular environment plays a role in Aβ-induced photoreceptor apoptosis. Subretinal injection of Aβ was followed by activation and migration of microglial cells and then by photoreceptor apoptosis. Microglial cells phagocytosed rhodopsin-containing debris and Aβ in the subretinal space. Quantitative RT-PCR allowed us to identify a specific gene expression profile associated with the Aβ-induced progression of retinal degeneration and consistent with oxidative stress, inflammation, and an apoptotic program. The gene most highly upregulated in Aβ-injected retinas was that for the chemokine CCL2, and its absence or that of its cognate receptor CCR2 greatly reduced migration of activated microglial cells to the site of retinal injury and profoundly worsened photoreceptor degeneration and disorganization of the retinal pigment epithelium in Aβ-injected retinas. Our study pinpoints the roles of Aβ and of CCL2/CCR2 axis-dependent inflammation in photoreceptor apoptosis.
authors.affiliation: Centre de Recherche des Cordeliers, Université Pierre et Marie Curie-Paris6, UMRS 872, F-75006 Paris, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Bruban
authors.forename: Agathe
authors.initials: A
authors.lastname: Maoui
authors.forename: Naïma
authors.initials: N
authors.lastname: Chalour
authors.forename: Na
authors.initials: N
authors.lastname: An
authors.forename: Laurent
authors.initials: L
authors.lastname: Jonet
authors.forename: Charles
authors.initials: C
authors.lastname: Feumi
authors.forename: Jacques
authors.initials: J
authors.lastname: Tréton
authors.forename: Florian
authors.initials: F
authors.lastname: Sennlaub
authors.forename: Francine
authors.initials: F
authors.lastname: Behar-Cohen
authors.forename: Frédéric
authors.initials: F
authors.lastname: Mascarelli
authors.forename: Virginie
authors.initials: V
authors.lastname: Dinet
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D018932:Chemokine CCL2 / Q000172:deficiency / Q000235:genetics*; D019610:Cytoprotection / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000633:toxicity*; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism* / Q000473:pathology*; D054390:Receptors, CCR2 / Q000172:deficiency / Q000235:genetics*
chemical_list: D016229:Amyloid beta-Peptides; C491766:Ccl2 protein, rat; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D010446:Peptide Fragments; D054390:Receptors, CCR2; C075222:amyloid beta-protein (1-42)