title: Microglial phagocytosis of living photoreceptors contributes to inherited retinal degeneration.
abstract: Retinitis pigmentosa, caused predominantly by mutations in photoreceptor genes, currently lacks comprehensive treatment. We discover that retinal microglia contribute non-cell autonomously to rod photoreceptor degeneration by primary phagocytosis of living rods. Using rd10 mice, we found that the initiation of rod degeneration is accompanied by early infiltration of microglia, upregulation of phagocytic molecules in microglia, and presentation of "eat-me" signals on mutated rods. On live-cell imaging, infiltrating microglia interact dynamically with photoreceptors via motile processes and engage in rapid phagocytic engulfment of non-apoptotic rods. Microglial contribution to rod demise is evidenced by morphological and functional amelioration of photoreceptor degeneration following genetic ablation of retinal microglia. Molecular inhibition of microglial phagocytosis using the vitronectin receptor antagonist cRGD also improved morphological and functional parameters of degeneration. Our findings highlight primary microglial phagocytosis as a contributing mechanism underlying cell death in retinitis pigmentosa and implicate microglia as a potential cellular target for therapy.
authors.affiliation: Unit on Neuron-Glia Interactions in Retinal Disease, National Eye institute National Institutes of Health, Bethesda, MD, USA.
authors.forename: Lian
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Unit on Neuron-Glia Interactions in Retinal Disease, National Eye institute National Institutes of Health, Bethesda, MD, USA.
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Zabel
authors.affiliation: Unit on Neuron-Glia Interactions in Retinal Disease, National Eye institute National Institutes of Health, Bethesda, MD, USA.
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Unit on Neuron-Glia Interactions in Retinal Disease, National Eye institute National Institutes of Health, Bethesda, MD, USA.
authors.forename: Wenxin
authors.initials: W
authors.lastname: Ma
authors.affiliation: Unit on Neuron-Glia Interactions in Retinal Disease, National Eye institute National Institutes of Health, Bethesda, MD, USA.
authors.forename: Parth
authors.initials: P
authors.lastname: Shah
authors.affiliation: Biological Imaging Core, National Eye institute National Institutes of Health, Bethesda, MD, USA.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Fariss
authors.affiliation: Visual Function Core, National Eye institute National Institutes of Health, Bethesda, MD, USA.
authors.forename: Haohua
authors.initials: H
authors.lastname: Qian
authors.affiliation: Department of Neuroscience and Physiology, Skirball Institute New York University School of Medicine, New York, NY, USA.
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Parkhurst
authors.affiliation: Department of Neuroscience and Physiology, Skirball Institute New York University School of Medicine, New York, NY, USA.
authors.forename: Wen-Biao
authors.initials: WB
authors.lastname: Gan
authors.affiliation: Unit on Neuron-Glia Interactions in Retinal Disease, National Eye institute National Institutes of Health, Bethesda, MD, USA wongw@nei.nih.gov.
authors.forename: Wai T
authors.initials: WT
authors.lastname: Wong
mesh_terms: D000818:Animals; D016923:Cell Death; D002465:Cell Movement; D004195:Disease Models, Animal; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors; D051379:Mice; D017628:Microglia / Q000502:physiology*; D061848:Optical Imaging; D010456:Peptides, Cyclic / Q000378:metabolism; D010587:Phagocytosis; D017948:Retinal Rod Photoreceptor Cells / Q000473:pathology*; D012174:Retinitis Pigmentosa / Q000151:congenital* / Q000473:pathology*
chemical_list: D039302:Integrin alphaVbeta3; D010456:Peptides, Cyclic; C507169:cyclic arginine-glycine-aspartic acid peptide
keywords: apoptosis; microglia; phagocytosis; retinal degeneration; retinitis pigmentosa