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CX3CR1-dependent subretinal microglia cell accumulation is associated with cardinal features of age-related macular degeneration
Open accessAbstract
The role of retinal microglial cells (MCs) in age-related macular degeneration (AMD) is unclear. Here we demonstrated that all retinal MCs express CX3C chemokine receptor 1 (CX3CR1) and that homozygosity for the CX3CR1 M280 allele, which is associated with impaired cell migration, increases the risk of AMD. In humans with AMD, MCs accumulated in the subretinal space at sites of retinal degeneration and choroidal neovascularization (CNV). In CX3CR1-deficient mice, MCs accumulated subretinally with age and albino background and after laser impact preceding retinal degeneration. Raising the albino mice in the dark prevented both events. The appearance of lipid-bloated subretinal MCs was drusen-like on funduscopy of senescent mice, and CX3CR1-dependent MC accumulation was associated with an exacerbation of experimental CNV. These results show that CX3CR1-dependent accumulation of subretinal MCs evokes cardinal features of AMD. These findings reveal what we believe to be a novel pathogenic process with important implications for the development of new therapies for AMD.
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In the citing paper
“Cx3cr1 knockout mice exhibited age-dependent subretinal microglial accumulation and retinal degeneration.37,38”
From CX3CR1 Deficiency Alters Microglial Activation and Reduces Beta-Amyloid Deposition in Two Alzheimer's Disease Mouse Models (2010) · cites this paper as [37]
In the citing paper
“In a French study, homozygosity for the CX3CR1 T280M allele was also reported to be associated with AMD (Combadiere et al., 2007).”
From Molecular pathology of age-related macular degeneration (2009) · cites this paper as Combadiere et al., 2007
In the citing paper
“whose immunohistochemical analysis in humans showed that CX3CR1 was expressed on all retinal microglial cells, and these cells are the only cells in the retina that express CX3CR1.”
From Molecular pathology of age-related macular degeneration (2009) · cites this paper as Combadiere et al., 2007
In the citing paper
“Their immunohistochemical analysis of AMD cases suggest that CX3CR1-positive microglial cells accumulated subretinally in affected areas of the macula”
From Molecular pathology of age-related macular degeneration (2009) · cites this paper as Combadiere et al., 2007
In the citing paper
“Moreover, Cx3cr1−/− mice exhibited increased microglial accumulation after laser-injury, as well as worsened laser-induced CNV and retinal degeneration.”
From Molecular pathology of age-related macular degeneration (2009) · cites this paper as Combadiere et al., 2007
In the citing paper
“Cx3cr1−/− mice demonstrated retinal degeneration and drusen-like deposits, which contained bloated accumulated microglia capable of phagocytosing outer segments of photoreceptor cells in 18 months and older mice.”
From Molecular pathology of age-related macular degeneration (2009) · cites this paper as Combadiere et al., 2007
In the citing paper
“The CX3CR1 SNP is associated with impaired microglial chemotaxis (Combadiere et al., 2007).”
From Molecular pathology of age-related macular degeneration (2009) · cites this paper as Combadiere et al., 2007
In the citing paper
“CX3CR1 positive cells in drusen and near CNV membranes are microglial cells in human AMD eyes (Combadiere et al., 2007).”
From Molecular pathology of age-related macular degeneration (2009) · cites this paper as Combadiere et al., 2007
In the citing paper
“Age-related macular degeneration (AMD) is associated with chronic inflammation [29, 65] and altered fecal microbial metabolite profiles [100].”
From Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain (2022) · cites this paper as [29]
In the citing paper
“homozygosity of the M280 allele showed defective cell migration and appeared to be associated with higher AMD susceptibility (30).”
From Unraveling a Multifactorial Late-Onset Disease: From Genetic Susceptibility to Disease Mechanisms for Age-Related Macular Degeneration (2009) · cites this paper as [30]
In the citing paper
“Homozygosity of the CX3CR1 M280 allele and V249I allele, associated with impaired microglial cell migration, has been shown to increase the risk of AMD (Combadiere et al., 2007; Tuo et al., 2004).”
From Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD) (2010) · cites this paper as Combadiere et al., 2007
In the citing paper
“At 12 months of age, ultrastructural analysis of senescent Cx3cr1−/− mice revealed subretinal cells that contained intracellular lipid deposits and outer segment remnants between the photoreceptor outer segment and RPE.”
From Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD) (2010) · cites this paper as Combadiere et al., 2007
In the citing paper
“At this age, the Cx3cr1−/− mice had significant (40%) thinning of the outer retina, mainly the outer nuclear layer, which progressed to marked degeneration of the photoreceptor layer by 4 months of age when compared to wild-type mice.”
From Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD) (2010) · cites this paper as Combadiere et al., 2007
In the citing paper
“At 18 months of age, the engorged subretinal microglial cells appeared drusen-like on fundoscopy (Combadiere et al., 2007).”
From Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD) (2010) · cites this paper as Combadiere et al., 2007
In the citing paper
“After laser injury, Cx3cr1−/− mice showed signs of significant CNV compared to wild-type mice (Combadiere et al., 2007).”
From Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD) (2010) · cites this paper as Combadiere et al., 2007
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BackgroundResultRegulation of Tau Pathology by the Microglial Fractalkine Receptor
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The Mouse Retina as an Angiogenesis Model
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ResultMolecular pathology of age-related macular degeneration
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BackgroundInfluentialImmunology of age-related macular degeneration
Ambati, J., Atkinson, J. P., & Gelfand, B. D. (2013) · Nature reviews. Immunology · doi:10.1038/nri3459 · Cited by 606
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Animal models of age related macular degeneration
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BackgroundInfluentialParainflammation, Chronic Inflammation and Age-Related Macular Degeneration
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BackgroundFractalkine and CX3CR1 regulate hippocampal neurogenesis in adult and aged rats
Bachstetter, A. D., Morganti, J. M., Jernberg, J., Schlunk, A., Mitchell, S. H., Brewster, K. W., Hudson, C. E., Cole, M. J., Harrison, J. K., Bickford, P. C., et al. (2011) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2009.11.022 · Cited by 364
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Uemura, A., Fruttiger, M., D'Amore, P. A., Falco, S. D., Joussen, A. M., Sennlaub, F., Brunck, L. R., Johnson, K. T. M., Lambrou, G. N., Rittenhouse, K. D., et al. (2021) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2021.100954 · Cited by 360
Self-citationRisk factors and biomarkers of age-related macular degeneration
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InfluentialSelf-citationRPE necroptosis in response to oxidative stress and in AMD
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Dry Age-Related Macular Degeneration: Mechanisms, Therapeutic Targets, and Imaging
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“The CX3CR1 polymorphisms result in decreased affinity for its ligand (CX3CL1), which in turn negatively affects microglial and macrophage migration.(122) In vitro studies suggest that accumulation of microglia due to impaired migration may cause direct damage to the photoreceptors.”
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“Although the role of retinal microglia in AMD is unclear, Combadiere et al. (2007) demonstrated that all retinal microglial cells express receptors for CX3C, a chemokine receptor 1 (CX3CR1).”
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“Because of a potential role of retinal microglia in AMD, variants in the chemokine receptor gene CX3CR1 were examined for association with AMD; homozygosity of the M280 allele showed defective cell migration and appeared to be associated with higher AMD susceptibility (30).”
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“Interestingly, these SNPs are linked to age-related diseases, with an increased risk for age-related macular degeneration [172,173] but with a reduced risk for atherosclerosis [174].”
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“It also has been reported that Cx3cr1 deficiency causes pronounced accumulation of activated microglia in retinas, leading to retinal macular degeneration (Combadière et al., 2007).”
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Aging is not a disease: Distinguishing age-related macular degeneration from aging
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“Knockouts of Cx3cr1, a G-protein coupled receptor involved in microglia activation and chemotaxis, result in retinal degeneration coincident with subretinal accumulation of microglia (Combadiere et al., 2007).”
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Rathnasamy, G., Foulds, W. S., Ling, E., & Kaur, C. (2018) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2018.05.006 · Cited by 250
“In these animals, microglia were found at the sites of future CNV prior to the onset of angiogenesis (Liu et al., 2013b), and expressed a variety of pro-angiogenic factors such as PDGF-β, FGF-1, FGF-2, and TGF-β1 (Li et al., 2017), ascertaining their influence in the initiation of pathological angiogenesis.”
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“Furthermore, CX3CR1 / microglia were shown to accumulate and promote retinal degeneration (Combadiere et al, 2007).”
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Neves, J., Zhu, J., Sousa‐Victor, P., Konjikusic, M. J., Riley, R. R., Chew, S., Qi, Y., Jasper, H., & Lamba, D. A. (2016) · Science · doi:10.1126/science.aaf3646 · Cited by 235
“Cx3Cr1 results in retinal degeneration in response to several stimuli and is associated with proinflammatory activation of immune cells (9, 14, 59).”
BackgroundAge related macular degeneration and drusen: Neuroinflammation in the retina
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“Data suggest that common variants of the cx3cr1 gene can lead to blunted CX3CR1 signaling and confer resistance or alleviate pathology in cardiovascular disease, age-related macular degeneration, and brain cancer (Combadière et al., 2007; Rodero et al., 2008; Apostolakis et al., 2009).”
BackgroundGautier, E. L., Jakubzick, C., & Randolph, G. J. (2009) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.108.180505 · Cited by 216
Melatonin in Alzheimer’s Disease
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“%) of the DAPI-positive cells isolated from CX3CR1+/GFP transgenic mice were also GFP-positive, indicating the expression of CX3CR1, a specific marker of microglia and dendritic cells in the retina [15] and the brain [35] (Fig.”
BackgroundInfluentialInflammation in the early stages of neurodegenerative pathology
Khandelwal, P. J., Herman, A. M., & Moussa, C. (2011) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2011.07.002 · Cited by 218
“Genetic variant with reduced levels of CX3CR1 is associated with age-related macular degeneration in humans (Combadiere et al., 2007).”
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“…retinal microglia in photoreceptor degeneration(Zhao et al., 2015), we investigated how CX3CR1 deficiency, a key regulator of microglial physiology (Combadiere et al., 2007; Liang et al., 2009), 1482 Volume 64, No. 9 influences microglial involvement and disease progression in the rd10 model for…”
BackgroundInfluentialEx Vivo Dynamic Imaging of Retinal Microglia Using Time-Lapse Confocal Microscopy
Lee, J. E., Liang, K. J., Fariss, R. N., & Wong, W. T. (2008) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.08-2076 · Cited by 212
Luhmann, U. F. O., Robbie, S. J., Munro, P., Barker, S. E., Durán, Y., Luong, V., Fitzke, F. W., Bainbridge, J. W., Ali, R. R., & MacLaren, R. E. (2009) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.09-3462 · Cited by 212
Regulation of Dynamic Behavior of Retinal Microglia by CX3CR1 Signaling
Liang, K. J., Lee, J. E., Wang, Y. D., Ma, W., Fontainhas, A. M., Fariss, R. N., & Wong, W. T. (2009) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.08-3357 · Cited by 220
“In mice lacking CX3CR1, retinal microglia accumulate aberrantly in the subretinal space with advancing age.(12,20) We reasoned that though defective CX3CR1 signaling in the long term culminates in the dislocation of microglia in the aged retina, CX3CR1 signaling in the short term may also influence constitutive dynami…”
Marchesi, F., Piemonti, L., Fedele, G., Destro, A., Roncalli, M. G., Albarello, L., Doglioni, C., Anselmo, A., Doni, A., Bianchi, P. P., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-1810 · Cited by 209
Gut microbiota influences pathological angiogenesis in obesity‐driven choroidal neovascularization
Andriessen, E. M., Wilson, A. M., Mawambo, G., Dejda, A., Miloudi, K., Sennlaub, F., & Sapieha, P. (2016) · EMBO Molecular Medicine · doi:10.15252/emmm.201606531 · Cited by 201
Self-citationMicroglia in the healthy and degenerating retina: Insights from novel mouse models
Karlstetter, M., Ebert, S., & Langmann, T. (2010) · Immunobiology · doi:10.1016/j.imbio.2010.05.010 · Cited by 197
“Since Cx3cr1 deficient microglia in the subretinal space preferentially secrete pro-inflammatory cytokines and chemokines, they may also recruit microglial precursors from the bloodstream (Combadiere et al., 2007).”
BackgroundDendritic cell physiology and function in the eye
Forrester, J. V., Xu, H., Kuffová, L., Dick, A. D., & McMenamin, P. G. (2010) · Immunological Reviews · doi:10.1111/j.0105-2896.2009.00873.x · Cited by 195
“This process has been reported to be even more prominent in the CCL2 ⁄CCR2 ⁄ ) mice (175), in Cx3cr1 ⁄ ) mice (176), and in double knockouts (177).”
BackgroundOn phagocytes and macular degeneration
Guillonneau, X., Eandi, C. M., Paques, M., Sahel, J.-A., Sapieha, P., & Sennlaub, F. (2017) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2017.06.002 · Cited by 185
“Raising albino Cx3cr1mice in darkness (Combadiere et al., 2007) or letti ng pigmented C57BL/6 Cx3cr1 mice age in very dim light conditions prevents the accumulation (Combadiere et al.”
BackgroundMethodResultInfluentialSelf-citationCerebral dysfunctions caused by sepsis during ageing
Manabe, T., & Heneka, M. T. (2022) · Nature Reviews Immunology · doi:10.1038/s41577-021-00643-7 · Cited by 191
Immune mechanisms in inflammatory and degenerative eye disease
Perez, V. L., & Caspi, R. R. (2015) · Trends in Immunology · doi:10.1016/j.it.2015.04.003 · Cited by 192
Rojas, B., Gallego, B., Ramirez, A. I., Salazar, J. J., de Hoz, R., Valiente‐Soriano, F. J., Avilés‐Trigueros, M., Villegas‐Pérez, M. P., Vidal‐Sanz, M., Triviño, A., et al. (2014) · Journal of Neuroinflammation · doi:10.1186/1742-2094-11-133 · Cited by 188
“Studies on retinal dystrophies, phototoxicity, and agerelated macular degeneration [61,85,87,89,93-97] have demonstrated that chronic activation of microglia could promote a pro-inflammatory environment that would affect RPE morphology and function [98,99].”
BackgroundJoyal, J., Gantner, M. L., & Smith, L. E. H. (2017) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2017.11.002 · Cited by 193
“Few suitable animal models replicate all aspects of AMD, but several transgenic mice present some characteristic signs of the disease (Table 1) (Ambati et al., 2003; Baba et al., 2010; Cao et al., 2010; Cashman et al., 2011; Chen et al., 2007; Combadière et al., 2007; Hahn et al., 2004; Heckenlively et al., 2003; Imam…”
BackgroundComplement Factor H Inhibits CD47-Mediated Resolution of Inflammation
Calippe, B., Augustin, S., Beguier, F., Charles-Messance, H., Poupel, L., Conart, J.-B., Hu, S. J., Lavalette, S., Fauvet, A., Rayes, J., et al. (2017) · Immunity · doi:10.1016/j.immuni.2017.01.006 · Cited by 168
“Early and advanced forms of AMD are associated with chronic accumulation of MPs in the subretinal space located between the RPE and photoreceptor outer segments (Combadière et al., 2007; Gupta et al., 2003; Lad et al., 2015; Levy et al., 2015a; Sennlaub et al., 2013).”
BackgroundInfluentialSelf-citationMediators of ocular angiogenesis
Qazi, Y., Maddula, S., & Ambati, B. K. (2009) · Journal of Genetics · doi:10.1007/s12041-009-0068-0 · Cited by 175
“2003) An association between ARMD and CXC3R1, a chemokine produced by microglia cells (MC), has also been observed (Combadiere et al. 2007).”
BackgroundZanzottera, E. C., Messinger, J. D., Ach, T., Smith, R. T., Freund, K. B., & Curcio, C. A. (2015) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.15-16431 · Cited by 164
“We discuss each RPE phenotype in turn, starting with cells newly described at end-stage AMD.”
BackgroundAbokyi, S., To, C. H., Lam, T. T., & Tse, D. Y. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/7901270 · Cited by 180
Microglia versus Monocytes: Distinct Roles in Degenerative Diseases of the Retina
Chen, Y., Roubeix, C., Sennlaub, F., & Saban, D. R. (2020) · Trends in Neurosciences · doi:10.1016/j.tins.2020.03.012 · Cited by 169
“Subretinal Space in Retinal Degenerative States Invasion of the photoreceptor layers and SRS by MNPs is a disease phenotype of IRDs and AMD [6, 14, 18, 19, 28].”
BackgroundInfluentialSelf-citationOxidative stress, innate immunity, and age-related macular degeneration
Shaw, P. X., Stiles, T. L., Douglas, C. R., Ho, D., Fan, W., Du, H., & Xu, X. (2016) · AIMS molecular science · doi:10.3934/molsci.2016.2.196 · Cited by 175
“They provide immune surveillance in the inner retina and have been associated with AMD [136,137].”
BackgroundImmunopathological aspects of age-related macular degeneration
Patel, M. M., & Chan, C. (2008) · Seminars in Immunopathology · doi:10.1007/s00281-008-0112-9 · Cited by 167
“T280M, have been implicated in a variety of diseases, including age-related diseases [81, 85 ].”
BackgroundInfluentialRetinal ultrastructure of murine models of dry age-related macular degeneration (AMD)
Ramkumar, H. L., Zhang, J., & Chan, C.-C. (2010) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2010.02.002 · Cited by 163
“Homozygosity of the CX3CR1 M280 allele and V249I allele, associated with impaired microglial cell migration, has been shown to increase the risk of AMD (Combadiere et al., 2007; Tuo et al., 2004).”
BackgroundTargeting the complement system for the management of retinal inflammatory and degenerative diseases
Xu, H., & Chen, M. (2016) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2016.03.001 · Cited by 168
“Examples of the immune modulatory mechanisms include (but are not limited to) the CD200-CD200R (Dick et al., 2003) and CX3CL1-CX3CR1 (Combadiere et al., 2007) pathway, thrombospondin-1, TGF-β , CTLA4, CTLA2, and various complement inhibitors (Horie et al., 2010; Kawazoe et al., 2012; Mochizuki et al., 2013; Sugita et…”
BackgroundBosco, A., Romero, C. O., Breen, K., Chagovetz, A. A., Steele, M. R., Ambati, B. K., & Vetter, M. L. (2015) · Disease Models & Mechanisms · doi:10.1242/dmm.018788 · Cited by 160
“…full anesthesia induced by inhalation of 2% (vol) Isoflurane in 2 liter/min oxygen, mice were transcardially perfused with 5 ml PBS followed by 20 ml 4% paraformaldehyde (PFA; Electron Microscopy Sciences, Hatfield, PA) in 0.1 M PBS circulated with a peristaltic pump (Dynamax, Rainin, Oakland, CA).”
MethodInfluentialRegulation of age-related macular degeneration-like pathology by complement factor H
Toomey, C. B., Kelly, U., Saban, D. R., & Rickman, C. B. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1424391112 · Cited by 157
Zhang, Y., Zhao, L., Wang, X., Ma, W., Lazere, A., Qian, H., Zhang, J., Abu-Asab, M. S., Fariss, R. N., Roger, J. E., et al. (2018) · Science Advances · doi:10.1126/sciadv.aap8492 · Cited by 145
“In the retina, where CX3CL1 is constitutively expressed by retinal neurons in the inner layers of the retina (14), CX3CL1-CX3CR1 signaling has been documented to mediate multiple aspects of microglial physiology, including process motility, microglial localization, and regulation of activation (15, 16), indicating tha…”
BackgroundReticular pseudodrusen: A critical phenotype in age-related macular degeneration
Wu, Z., Fletcher, E. L., Kumar, H., Greferath, U., & Guymer, R. H. (2021) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2021.101017 · Cited by 147
Joly, S., Francke, M., Ulbricht, E., Beck, S. C., Seeliger, M. W., Hirrlinger, P. G., Hirrlinger, J., Lang, K. S., Zinkernagel, M. S., Odermatt, B., et al. (2009) · American Journal Of Pathology · doi:10.2353/ajpath.2009.090023 · Cited by 152
Schnichels, S., Paquet‐Durand, F., Löscher, M., Tsai, T., Hurst, J., Joachim, S. C., & Klettner, A. (2020) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2020.100880 · Cited by 152
Age-related Macular Degeneration: Genetic and Environmental Factors of Disease
Chen, Y., Bedell, M., & Zhang, K. (2010) · Molecular Interventions · doi:10.1124/mi.10.5.4 · Cited by 143
Diabetic retinopathy and dysregulated innate immunity
Xu, H., & Chen, M. (2017) · Vision Research · doi:10.1016/j.visres.2017.04.013 · Cited by 144
“These retinal cells express various immune modulators that can suppress mye- Please cite this article in press as: Xu, H., & Chen, M. Diabetic retinopathy and 10.1016/j.visres.2017.04.013 loid cell (microglia/macrophage) activation via the CD200CD200R (Dick et al., 2003) or CX3CL1-CX3CR1 (Combadiere et al., 2007) path…”
BackgroundInfluentialLavalette, S., Raoul, W., Houssier, M., Camelo, S., Levy, O., Calippe, B., Jonet, L., Béhar‐Cohen, F., Chemtob, S., Guillonneau, X., et al. (2011) · American Journal Of Pathology · doi:10.1016/j.ajpath.2011.01.013 · Cited by 138
Self-citationLevy, O., Calippe, B., Lavalette, S., Hu, S. J., Raoul, W., Dominguez, E., Housset, M., Pâques, M., Sahel, J., Bemelmans, A., et al. (2015) · EMBO Molecular Medicine · doi:10.15252/emmm.201404524 · Cited by 143
“Cx3cr1 deficiency in mice leads to a strong increase of subretinal MP accumulation with age, after light challenge or laser injury (Combadiere et al, 2007; Raoul et al, 2008; Ma et al, 2009), in A B C D E F G H Figure 1.”
BackgroundInfluentialSelf-citationOxidative Stress and Antioxidants in Age-Related Macular Degeneration
Kushwah, N. S., Bora, K., Maurya, M., Pavlovich, M. C., & Chen, J. (2023) · Antioxidants · doi:10.3390/antiox12071379 · Cited by 140
Mechanism of Inflammation in Age-Related Macular Degeneration
Parmeggiani, F., Romano, M., Costagliola, C., Semeraro, F., Incorvaia, C., D’Angelo, S., Perri, P., Palma, P. D., Nadai, K. D., & Sebastiani, A. (2012) · Mediators of Inflammation · doi:10.1155/2012/546786 · Cited by 140
Hoh Kam, J., Lenassi, E., & Jeffery, G. (2010) · PLoS ONE · doi:10.1371/journal.pone.0013127 · Cited by 131
Simmons, G. W., Pong, W. W., Emnett, R. J., White, C. R., Gianino, S. M., Rodriguez, F. J., & Gutmann, D. H. (2010) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3182032d37 · Cited by 130
“CX3CL1 acts on its receptor, CX3CR1, to regulate microglia migration and function (46), and loss of CX3CR1 expression has been reported to lead to subretinal microglia cell accumulation (47).”
Modulation of three key innate immune pathways for the most common retinal degenerative diseases
Akhtar‐Schäfer, I., Wang, L., Krohne, T. U., Xu, H., & Langmann, T. (2018) · EMBO Molecular Medicine · doi:10.15252/emmm.201708259 · Cited by 129
Microglia: Key Players in Retinal Ageing and Neurodegeneration
Guo, L., Choi, S., Bikkannavar, P., & Cordeiro, M. F. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.804782 · Cited by 134
“Additionally, such subretinal microglial accumulation seen in the CXCR1−/− mice was associated with retinal degeneration including photoreceptor loss (Combadière et al., 2007).”
BackgroundInfluentialRetinal microglia: Functions and diseases
Fan, W., Huang, W., Chen, J., Li, N., Mao, L., & Hou, S. (2022) · Immunology · doi:10.1111/imm.13479 · Cited by 139
“CX3CR1/CX3CL1 signalling physiologically protects neurons and maintains homeostasis, while aged CX3CR1-deficient mice display subretinal microglial accumulation, drusen-like deposits and associated photoreceptor degeneration, which are hallmarks of AMD [114,115].”
BackgroundThe role of glia in retinal vascular disease
Coorey, N. J., Shen, W., Chung, S. H., Zhu, L., & Gillies, M. C. (2012) · Clinical and Experimental Optometry · doi:10.1111/j.1444-0938.2012.00741.x · Cited by 136
Xue, C., Chen, K., Gao, Z., Bao, T., Dong, L., Zhao, L., Tong, X., & Li, X. (2023) · Cell Communication and Signaling · doi:10.1186/s12964-022-01016-w · Cited by 146
“Others include perivascular macrophages, persistent transparent cells and DCs. Hyperglycemia inhibits the activation of myeloid cells (microglia/macrophages) and T cells, but it can induce Tregs cells formation through CD200-CD200R or CX3CLL-CX3CRL pathway [179, 180].”
BackgroundCurcumin: Therapeutical Potential in Ophthalmology
Pescosolido, N., Giannotti, R., Plateroti, A. M., Pascarella, A., & Nebbioso, M. (2013) · Planta Medica · doi:10.1055/s-0033-1351074 · Cited by 126
Choroid Sprouting Assay: An Ex Vivo Model of Microvascular Angiogenesis
Shao, Z., Friedlander, M. S. H., Hurst, C. G., Cui, Z., Pei, D. T., Evans, L. P., Juan, A. M., Tahir, H., Duhamel, F., Chen, J., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0069552 · Cited by 125
“The latter observations were consistent with what appears to occur in choroidal neovascularization in vivo [22].”
ResultSelf-citationRutar, M., Natoli, R., & Provis, J. M. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-221 · Cited by 125
“Modulation of exaggerated chemokine responses using siRNA may have value in reducing inflammation-mediated cell death in retinal degenerative disease such as AMD.”
BackgroundInfluentialThe microglia in healthy and diseased retina
Li, L., Eter, N., & Heiduschka, P. (2015) · Experimental Eye Research · doi:10.1016/j.exer.2015.04.020 · Cited by 112
Puntambekar, S. S., Moutinho, M., Lin, P. B.-C., Jadhav, V., Tumbleson-Brink, D., Balaji, A., Benito, M. A., Xu, G., Oblak, A., Lasagna-Reeves, C. A., et al. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00545-9 · Cited by 113
Phagocyte dysfunction, tissue aging and degeneration
Li, W. (2013) · Ageing Research Reviews · doi:10.1016/j.arr.2013.05.006 · Cited by 116
The innate immune system in diabetic retinopathy
Pan, W. W., Lin, F., & Fort, P. E. (2021) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2021.100940 · Cited by 117
Zanzottera, E. C., Ach, T., Huisingh, C., Messinger, J. D., Spaide, R. F., & Curcio, C. A. (2016) · Retina · doi:10.1097/iae.0000000000001276 · Cited by 117
Choroideremia: New Findings from Ocular Pathology and Review of Recent Literature
MacDonald, I. M., Russell, L., & Chan, C. (2009) · Survey of Ophthalmology · doi:10.1016/j.survophthal.2009.02.008 · Cited by 117
“Recent investigation in an AMD model of deficient mice has raised the hypothesis that subretinal microglia accumulation, resulting from a migratory defect associated with CX3CR1, plays a key role in drusen formation, choroidal neovascularization, and retinal degeneration—the main features of AMD.(6) Further research s…”
BackgroundInfluentialZanzottera, E. C., Messinger, J. D., Ach, T., Smith, R. T., & Curcio, C. A. (2015) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.15-16432 · Cited by 110
A Linkage between Angiogenesis and Inflammation in Neovascular Age-Related Macular Degeneration
Heloterä, H., & Kaarniranta, K. (2022) · Cells · doi:10.3390/cells11213453 · Cited by 121
“This study also revealed that activated subretinal microglials express VEGF-A, exacerbate neovascularization and retinal degeneration [103].”
BackgroundReduced microglial CX3CR1 expression delays neurofibromatosis‐1 glioma formation
Pong, W. W., Higer, S. B., Gianino, S. M., Emnett, R. J., & Gutmann, D. H. (2012) · Annals of Neurology · doi:10.1002/ana.23813 · Cited by 114
“CX3CR1 variants have been found to contribute to defective adhesive function, fractalkine binding, signaling,(19) and impaired migration.(20) Taken together, these findings support a model in which chemokine-regulated microglia function represents a prime determinant of glioma biology.”
BackgroundAnimal Models of Retinal Disease
Fletcher, E. L., Jobling, A. I., Vessey, K. A., Luu, C. D., Guymer, R. H., & Baird, P. N. (2011) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-384878-9.00006-6 · Cited by 111
“A second group of animal models have been developed that carry mutations affecting chemokines or chemokine receptors.(211,212) monocyte chemoattractant protein-1 (MCP-1) or Chemokine 2 (CCl2) is a chemokine that is important for monocyte signaling and recruitment.”
BackgroundInfluentialLiu, J., Copland, D. A., Horie, S., Wei-kang, W., Chen, M., Xu, Y., Morgan, B. P., Mack, M., Xu, H., Nicholson, L. B., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0072935 · Cited by 111
Metadata
- Authors
- Combadière, C., Feumi, C., Raoul, W., Keller, N., Rodéro, M., Pézard, A., Lavalette, S., Houssier, M., Jonet, L., Picard, E., Debré, P., Sirinyan, M., Deterre, P., Ferroukhi, T., Cohen, S.-Y., Chauvaud, D., Jeanny, J.-C., Chemtob, S., Behar-Cohen, F., & Sennlaub, F.
- Affiliations
- Inserm (FR)
- Centre de Recherche des Cordeliers (FR)
- Centre Hospitalier Universitaire Sainte-Justine (CA)
- Assistance Publique – Hôpitaux de Paris (FR)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2007-10-01
- Volume
- 117
- Issue
- 10
- Pages
- 2920-2928
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC1994614
- OpenAlex
- W2122311980
- Cited by
- 618
- References
- 48
- Citations by year
- 2026: 14 · 2025: 28 · 2024: 37 · 2023: 28 · 2022: 39 · 2021: 45 · 2020: 38 · 2019: 25 · 2018: 39 · 2017: 22 · 2016: 32 · 2015: 45 · 2014: 29 · 2013: 45 · 2012: 36
- FWCI
- 27.59
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- HAL (submittedVersion, other-oa)
- HAL (submittedVersion, cc-by-nc-sa)
- Funders
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Health Sciences › Medicine › Ophthalmology › Retinal Development and Disorders
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Retinal Imaging and Analysis
- Keywords
- age-related macular degeneration, retinal microglia, CX3CR1, choroidal neovascularization, drusen, microglial migration, retinal degeneration, microglial senescence, dark rearing
- MeSH terms
- CX3C Chemokine Receptor 1, Alleles, Animals, Cell Movement, Homozygote, Humans, Macular Degeneration, Male, Polymorphism, Genetic, Retina, Retinal Drusen, Microglia, Mice, Knockout, Receptors, Chemokine, Choroidal Neovascularization, Mice
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