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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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“Previous studies have shown that ‘‘drusen-like’’ changes in aged CCL2 KO mice [38] and cx3cr1 KO mice [21] are subretinal macrophages.”
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“More recent findings suggest a role for immunologic processes in AMD pathogenesis, including recruitment of macrophages,(4) involvement of systemic inflammatory processes, complement activation, and microglial activation and accumulation.(13) Historically, macrophages have been observed at sites of CNV in patients wit…”
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“It has been reported that macrophages and microglia are accumulated in surgically excised CNV tissue (Oh et al., 1999) and in the affected areas of JOURNAL OF CELLULAR PHYSIOLOGY human eyes with AMD (Combadiere et al., 2007).”
BackgroundControl of Chemokine Gradients by the Retinal Pigment Epithelium
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“From the very recent literature, we know that fractalkine is involved in the pathogenesis of several clinical diseases including chronic pancreatitis [13,14], atherosclerosis, rheumatoid arthritis, glomerulonephritis, HIV disease, allograft rejection [15], age-related macular degeneration [16], uveitis [17], neuropath…”
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[WITHDRAWN] Retinal Vasculature in Development and Diseases
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RetractedREVIEW PAPER: Animals as Models of Age-Related Macular Degeneration
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“Single-nucleotide polymorphisms (SNPs) in the CX3CR1 gene confer increased risk of AMD.(12,15,109) CX3CR1-positive cells in drusen have been identified as microglial cells, thus implicating this cell type in the pathogenesis of AMD in human eyes.”
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APOE Isoforms Control Pathogenic Subretinal Inflammation in Age-Related Macular Degeneration
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“The mice were raised under 12 h light/12 h dark cycles at 100 –500 lux at the cage level, with no additional cover in the cage, the conditions that induce MP accumulation in Cx3cr1-deficient mice with age (Combadière et al., 2007).”
BackgroundMethodInfluentialSelf-citationCcl2/Cx3cr1-Deficient Mice: An Animal Model for Age-Related Macular Degeneration
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“Interestingly, Cx3cr1 -deficient mice have recently been reported to develop AMD-like features including ‘drusen’ formation, progressive accumulation of subretinal microglia and photoreceptor degeneration in aged animals [”
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Self-citationExclusive CX3CR1 dependence of kidney DCs impacts glomerulonephritis progression
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“Activated microglia have been found in the outer retina and subretinal space in eyes with AMD.(34,76) Retinal microglia express the chemokine receptor CX3CR1.”
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“Homozygous Cx3cr1tm1Litt [425] and Cx3cr1tm1Zm [426] mice on the same C57BL/6J background showed similar rates of PR degeneration with 30% and 40% loss, respectively, at 16–18 months of age.”
BackgroundInfluentialIL-33 amplifies an innate immune response in the degenerating retina
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“Intriguingly, Cx3cr1-null mice have large bloated microglia in the subretinal space, similar to those seen in patients with AMD.(46) It was hypothesized that loss of Cx3cr1 function leads to failure of regression of subretinal microgia, leading to photoreceptor death and neovascularization.”
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“Third, a genetic variant with reduced levels of CX3CR1 has been associated with the age-related macular degeneration in humans (Combadiere et al., 2007).”
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“…degeneration, including age-related macular degeneration and inherited forms such as retinitis pigmentosa, are characterized by microglial activation and pro-inflammatory microenvironments (Cao et al., 2011; Combadière et al., 2007; Gupta et al., 2003; Yoshida et al., 2013; Zeng et al., 2005).”
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“Studies involving experimental models of choroidal neovascularization have shown that macrophage inhibition induced through liposomal clodronate 55,56 or deficiency in the fractalkine chemokine receptor (CX3CR1) 57 reduces the resulting lesion size.”
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“Many HRCs indeed show cytological characteristics very close to those of RPE cells; at the same time, the unequivocal presence of subretinal and sub-RPE cells expressing macrophage markers, identified using immunohistological markers such as CD163, IBA-1 and CCR2 (Sennlaub et al., 2013; Combadière et al., 2007), have…”
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“In CX3CR1-deficient (CX3CR1) mice, MCs and drusen-like deposits accumulated subretinally with age [85].”
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Inflammatory signals from photoreceptor modulate pathological retinal angiogenesis via c-Fos
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“In degenerative diseases, this breakdown in the immune privilege may be a compensatory response to maintain vision because impaired microglial migration into or out of the subretinal space promotes photoreceptor cell death (Combadière et al., 2007; Chen et al., 2011b).”
BackgroundComplement expression in retinal pigment epithelial cells is modulated by activated macrophages
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Inflammation and the pathogenesis of age-related macular degeneration
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“Homozygosity for the CX3CR1 M280 allele, associated with impaired cell migration, increases the risk of AMD [58].”
BackgroundThe Oxygen Paradox, the French Paradox, and age-related diseases
Davies, J. M. S., Cillard, J., Friguet, B., Cadenas, E., Cadet, J., Cayce, R., Fishmann, A., Liao, D., Bulteau, A.-L., Derbré, F., et al. (2017) · GeroScience · doi:10.1007/s11357-017-0002-y · Cited by 82
Self-citationCX3CR1 Reduces Kidney Fibrosis by Inhibiting Local Proliferation of Profibrotic Macrophages
Engel, D. R., Krause, T. A., Snelgrove, S. L., Thiebes, S., Hickey, M. J., Boor, P., Kitching, A. R., & Kurts, C. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1402149 · Cited by 85
“Also, CX3CR1 has been implicated in monocyte recruitment into inflamed tissues, like arteriosclerotic vessels (45), the listeria-infected spleen (46), the eye (47), in colitis models (28), or the skin (48).”
BackgroundFractalkine receptor regulates microglial neurotoxicity in an experimental mouse glaucoma model
Wang, K., Peng, B., & Lin, B. (2014) · Glia · doi:10.1002/glia.22715 · Cited by 82
“Similarly, Cx3cr1 deficiency causes pronounced accumulation of activated microglia leading to retinal macular degeneration (Combadiere et al., 2007).”
BackgroundKohno, H., Maeda, T., Perusek, L., Pearlman, E. M., & Maeda, A. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1301738 · Cited by 82
“Understanding the role of chemokines in retinal degeneration is particularly important because they not only dictate the migration of inflammatory cells, they are also potential drivers of retinal degenerative conditions in humans and mice (5, 6).”
BackgroundGenetics of Immunological and Inflammatory Components in Age-related Macular Degeneration
Tuo, J., Grob, S., Zhang, K., & Chan, C. (2012) · Ocular Immunology and Inflammation · doi:10.3109/09273948.2011.628432 · Cited by 80
Zhang, M., Xu, G., Liu, W. D., Ni, Y., & Zhou, W. (2012) · PLoS ONE · doi:10.1371/journal.pone.0035446 · Cited by 80
“The reasons for these differences are not quite clear, but it has been hypothesized that CX3CR1 activates different signaling pathways in different situations [65].”
Cochain, C., Rodero, M. P., Vilar, J., Récalde, A., Richart, A. L., Loinard, C., Zouggari, Y., Guérin, C. L., Duriez, M., Combadière, B., et al. (2010) · Cardiovascular Research · doi:10.1093/cvr/cvq153 · Cited by 85
“CX3CR1-expressing cells also exacerbates retinal neovascularization in a murine model of age-related macular degeneration, presumably through VEGF expression.(13) Additionally, a population of Tie2expressing monocytes, belonging to the Ly6C subset, has been shown to promote tumour angiogenesis.”
BackgroundSelf-citationAn engineered CX3CR1 antagonist endowed with anti-inflammatory activity
Dorgham, K., Ghadiri, A., Hermand, P., Rodero, M. P., Poupel, L., Iga, M., Hartley, O., Gorochov, G., Combadière, C., & Déterre, P. (2009) · Journal of Leukocyte Biology · doi:10.1189/jlb.0308158 · Cited by 82
“The genetic ablation of mCX3CR1 leads to decreased atherogenesis but to increased brain inflammation and pain facilitation [10– 13], to increased microglial neurotoxicity [14], and to early AMD [15].”
BackgroundInfluentialSelf-citationAccumulation of murine subretinal macrophages: effects of age, pigmentation and CX3CR1
Chinnery, H. R., McLenachan, S., Humphries, T. G., Kezic, J. M., Chen, X., Ruitenberg, M. J., & McMenamin, P. G. (2011) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2011.03.010 · Cited by 82
“…absence of CX3CR1 has been previously reported to esult in complete outer retinal degeneration in BALB/c ice by 4 months of age accompanied by the presence of arge numbers of SRMO and in aged (18-month-old) 57BL/6 CX3CR1-deficient mice, thinning of the retina as reported (Combadiere et al., 2007).”
BackgroundResultInfluentialRodero, M. P., Marie, Y., Coudert, M., Blondet, E., Mokhtari, K., Rousseau, A., Raoul, W., Carpentier, C., Sennlaub, F., Déterre, P., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2008.17.2833 · Cited by 76
“Moreover, we recently showed that CX3CR1-dependent subretinal microglial cell accumulation leads to cardinal features of age-related macular degeneration.(15) The role of these chemokines and their receptors in brain tumors is not known.”
BackgroundMethodInfluentialSelf-citationMore than meets the eye: The role of microglia in healthy and diseased retina
Murenu, E., Gerhardt, M.-J., Biel, M., & Michalakis, S. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1006897 · Cited by 73
Changes in Retinal Glial Cells with Age and during Development of Age-Related Macular Degeneration
Telegina, D. V., Kozhevnikova, O. S., & Kolosova, N. G. (2018) · Biochemistry (Moscow) · doi:10.1134/s000629791809002x · Cited by 78
Nielsen, M. K., Subhi, Y., Molbech, C. R., Falk, M. K., Nissen, M. H., & Sørensen, T. L. (2019) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.18-25878 · Cited by 79
“Mononuclear phagocytes (microglia and blood-derived macrophages) are thought to play a central role in GA as they are found accumulated within the atrophic area of donor eyes.(35,36) These cells change in phenotype according to the surrounding microenvironment.”
BackgroundMelatonin Therapy in Patients with Alzheimer’s Disease
Cardinali, D. P., Vigo, D. E., Olivar, N., Vidal, M., & Brusco, L. I. (2014) · Antioxidants · doi:10.3390/antiox3020245 · Cited by 74
“An important factor in the pathogenesis of AD is the activation of microglia resulting in a higher level of expression of proinflammatory cytokines [112–115].”
BackgroundMa, W., Zhao, L., & Wong, W. T. (2011) · Advances in experimental medicine and biology · doi:10.1007/978-1-4614-0631-0_6 · Cited by 73
“…and/or CCL2 have been genetically ablated, activated microglia have also been found to accumulate in the subretinal space and become associated with drusenlike accumulations, RPE degeneration, photoreceptor atrophy, and choroidal neovascularization (CNV) (Combadiere et al. 2007; Tuo et al. 2007).”
BackgroundKrause, T. A., Alex, A. F., Engel, D. R., Kurts, C., & Eter, N. (2014) · PLoS ONE · doi:10.1371/journal.pone.0094313 · Cited by 72
“Indeed, microglia cells have been reported to translocate from the inner retina to the subretinal space both in laser-induced CNV and in humans with AMD [5].”
BackgroundInfluentialDifferential turnover rates of monocyte-derived cells in varied ocular tissue microenvironments
Kezic, J. M., & McMenamin, P. G. (2008) · Journal of Leukocyte Biology · doi:10.1189/jlb.0308166 · Cited by 71
“In addition to the potential role of choroidal macrophages, the discovery of age-dependent accumulation of subretinal microglia has recently implicated this population of cells as potential initiators of neovascularization and photoreceptor damage [14, 15].”
BackgroundInfluentialCX3CR1 deficiency promotes muscle repair and regeneration by enhancing macrophage ApoE production
Arnold, L., Perrin, H., de Chanville, C. B., Saclier, M., Hermand, P., Poupel, L., Guyon, E., Licata, F., Carpentier, W., Vilar, J., et al. (2015) · Nature Communications · doi:10.1038/ncomms9972 · Cited by 78
Self-citationAlves, C. H., Fernandes, R., Santiago, A. R., & Ambrósio, A. F. (2020) · Cells · doi:10.3390/cells9051217 · Cited by 73
“However, in CX3CR1-deficient mice, accumulation of microglial cells is also observed in the subretinal space at sites of retinal degeneration and is associated with an exacerbation of CNV [161].”
BackgroundAge-Related Retinal Changes in Wild-Type C57BL/6J Mice Between 2 and 32 Months
Ferdous, S., Liao, K. L., Gefke, I. D., Summers, V. R., Wu, W., Donaldson, K. J., Kim, Y.-K., Sellers, J. T., Dixon, J. A., Shelton, D. A., et al. (2021) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.62.7.9 · Cited by 70
Chen, Y., Lad, E. M., Mathew, R., Shiraki, N., Littleton, S., Chen, Y., Hou, J., Schlepckow, K., Degan, S., Chew, L. A., et al. (2024) · The Journal of Experimental Medicine · doi:10.1084/jem.20231011 · Cited by 72
“Considering the critical role of Cx3cr1 in regulating microglial function and sensitivity to light-induced retinal degeneration (Combadière et al., 2007; Ye et al., 2020), we only used Cx3cr1 YFP-CreER heterozygous mice hereafter and tested subjecting these mice to the LD model.”
BackgroundMethodSDF-1/CXCR4 Contributes to the Activation of Tip Cells and Microglia in Retinal Angiogenesis
Unoki, N., Murakami, T., Nishijima, K., Ogino, K., van Rooijen, N., & Yoshimura, N. (2010) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.09-4978 · Cited by 70
Zhao, M., Mantel, I., Gélizé, E., Li, X., Xie, X., Arboleda, A., Séminel, M., Levy, R., Dernigoghossian, M., Prunotto, A., et al. (2019) · Nature Communications · doi:10.1038/s41467-018-08125-6 · Cited by 72
Inflammatory choroidal neovascular membrane in posterior uveitis-pathogenesis and treatment
Dhingra, N., Kelly, S., Majid, M., Bailey, C., & Dick, A. D. (2009) · Indian Journal of Ophthalmology · doi:10.4103/0301-4738.58467 · Cited by 69
“[25] Age d mice knockouts for CX3CR1 also sporadically develop drusen-like lesions, progressive accumulation of subretinal microglia, and photoreceptor degeneration.[26]”
Camelo, S. (2014) · Autoimmune Diseases · doi:10.1155/2014/532487 · Cited by 72
“Therefore CX3CR1-dependent 2 Autoimmune Diseases regulation of monocytes/ MΦ recruitment in the subretinal space appears to be involved in the development of both wet and dry AMD [22, [26] [27] [28] [29] [30] .”
BackgroundInfluentialFeldman, G. J., Parvizi, J., Levenstien, M. A., Scott, K., Erickson, J. A., Fortina, P. M., Devoto, M., & Peters, C. L. (2013) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.1999 · Cited by 74
“In 2007, Combadière and colleagues((32)) found that homozygosity for the CX3CR1 M280 allele was consistently more frequent in AMD patients compared to controls, observing that impaired migration of microglial cells occurred in affected patients.”
BackgroundTime course of bilateral microglial activation in a mouse model of laser-induced glaucoma
Ramirez, A. I., de Hoz, R., Fernández‐Albarral, J. A., Salobrar‐García, E., Rojas, B., Valiente‐Soriano, F. J., Avilés‐Trigueros, M., Villegas‐Pérez, M. P., Vidal‐Sanz, M., Triviño, A., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-61848-9 · Cited by 69
The Role of Osteopontin in Microglia Biology: Current Concepts and Future Perspectives
Rosmus, D.-D., Lange, C., Ludwig, F., Ajami, B., & Wieghofer, P. (2022) · Biomedicines · doi:10.3390/biomedicines10040840 · Cited by 70
“Histopathological studies have demonstrated that microglia accumulate in the subretinal space (SRS) of AMD donor eyes and exhibit a rather amoeboid, activated morphology [202,203].”
BackgroundRecent developments in the management of dry age-related macular degeneration
Buschini, E., Zola, M., Fea, A. M., Lavia, C. A., Nassisi, M., Pignata, G., & Grignolo, F. M. (2015) · Clinical ophthalmology · doi:10.2147/opth.s59724 · Cited by 67
“For example, microglia and macrophages, in order to modulate its recruitment to the site of injury, or mast cells, to prevent its degranulation.(67,68) To date, our knowledge on the role of inflammation and immune system is fairly advanced.”
BackgroundChen, M., Zhao, J., Luo, C., Pandi, S. P. S., Peñalva, R. G., Fitzgerald, D. C., & Xu, H. (2012) · Glia · doi:10.1002/glia.22315 · Cited by 66
“Age-related retinal degeneration along with increased microglial activation has been observed in CX3CR1deficient mice (Combadiere et al., 2007) and CCL2/ CX3CR1 dual-deficient mice (Tuo et al.”
BackgroundKim, G. H., Kim, H., Paik, S.-S., Jung, S. W., Kang, S., & Kim, I. (2016) · Graefe s Archive for Clinical and Experimental Ophthalmology · doi:10.1007/s00417-015-3258-x · Cited by 67
A Perspective of AMD Through the Eyes of Immunology
Copland, D. A., Theodoropoulou, S., Liu, J., & Dick, A. D. (2018) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.18-23893 · Cited by 66
“However, the corollary is that sustained inflammasome activation will also damage tissues, as seen in the pathogenesis of autoinflammatory disorders and implicated in AD, cancer, diabetes, and AMD.33,107,108 Understanding the regulatory mechanisms controlling inflammasome activation, and specifically how signals from…”
BackgroundInfluentialShiose, S., Chen, Y., Okano, K., Roy, S., Kohno, H., Tang, J. C. O., Pearlman, E. M., Maeda, T., Palczewski, K., & Maeda, A. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.228551 · Cited by 66
VEGF in Diabetic Retinopathy and Age-Related Macular Degeneration
Callan, A., Heckman, J., Tah, G., Lopez, S., Valdez, L., & Tsin, A. T. C. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26114992 · Cited by 76
“In the M1 state, microglia have shown to increase expression of injury responsive genes and decrease expression of homeostatic checkpoint genes like CX3CR1 [32].”
Zając-Pytrus, H. M., Pilecka, A., Turno‐Kręcicka, A., Adamiec-Mroczek, J., & Misiuk‐Hojło, M. (2015) · Advances in Clinical and Experimental Medicine · doi:10.17219/acem/27093 · Cited by 65
Yang, X., Hu, J., Zhang, J., & Guan, H. (2010) · British Journal of Ophthalmology · doi:10.1136/bjo.2009.165811 · Cited by 64
“Accumulation of microglia cells in the subretinal space may be a driving force in the pathogenesis of AMD.(5) CX3CR1 is expressed on retinal microglia cells and plays an important role in the activation and migration of the microglia.”
BackgroundMethodInfluentialTargeting Microglia to Treat Degenerative Eye Diseases
Wang, S. K., & Cepko, C. L. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.843558 · Cited by 66
“Following laser injury to induce CNV, mice with CX3CR1 knocked out exhibited larger lesions than those with intact expression (15).”
BackgroundMaurya, M., Bora, K., Blomfield, A. K., Pavlovich, M. C., Huang, S., Liu, C.-H., & Chen, J. (2023) · Neural Regeneration Research · doi:10.4103/1673-5374.369098 · Cited by 63
“These include inflammation ( Cfh –/– and/or Cx3cr1 –/– mice) (Coffey et al., 2007; Combadiere et al., 2007), impaired lipid function (transgenic ApoE4 with high-fat diet, and macrophage-specific ABCA1 and ABCG1 deficiency) (Ramkumar et al., 2010; Ban et al., 2018), and oxidative stress and defense…”
Gnanaguru, G., Choi, A. R., Amarnani, D., & D'Amore, P. A. (2016) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.15-18663 · Cited by 65
“13,19,20,38,39 Oxidized lipids have been shown to accumulate preferentially in the macula of human eyes with AMD.”
Juel, H. B., Faber, C., Udsen, M. S., Folkersen, L., & Nissen, M. H. (2012) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.12-9963 · Cited by 62
Wang, S. K., Xue, Y., Rana, P. C., Hong, C. M., & Cepko, C. L. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1901787116 · Cited by 63
“In healthy eyes, CX3CR1, the only known receptor for CX3CL1, is thought to be specifically expressed by microglia (65).”
BackgroundRoss, R. J., Zhou, M., Shen, D., Fariss, R. N., Ding, X., Bojanowski, C. M., Tuo, J., & Chan, C.-C. (2008) · Experimental Eye Research · doi:10.1016/j.exer.2008.01.014 · Cited by 60
Progress in developing rodent models of age-related macular degeneration (AMD)
Pandi, S. P. S., Ratnayaka, J. A., Lotery, A. J., & Teeling, J. L. (2020) · Experimental Eye Research · doi:10.1016/j.exer.2020.108404 · Cited by 63
Different Therapeutic Approaches for Dry and Wet AMD
Marchesi, N., Capierri, M., Pascale, A., & Barbieri, A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252313053 · Cited by 66
Raoul, W., Feumi, C., Keller, N., Lavalette, S., Houssier, M., Béhar‐Cohen, F., Combadière, C., & Sennlaub, F. (2008) · Ophthalmic Research · doi:10.1159/000119860 · Cited by 61
“retinal MCs. Supporting the hypothesis that degenerating MCs contribute to drusen formation inserm-00315944, version 1 - 1 Sep 2008 is the fact that CX3CR1 deposits can be found in drusen in AMD patients ( 1 ).”
BackgroundInfluentialSelf-citationHallam, T. M., Marchbank, K. J., Harris, C. L., Osmond, C., Shuttleworth, V. G., Griffiths, H., Cree, A. J., Kavanagh, D., & Lotery, A. J. (2020) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.61.6.18 · Cited by 57
Differential Modulation of Retinal Degeneration by Ccl2 and Cx3cr1 Chemokine Signalling
Luhmann, U. F. O., Lange, C., Robbie, S. J., Munro, P., Cowing, J. A., Armer, H. E. J., Luong, V., Carvalho, L. S., MacLaren, R. E., Fitzke, F. W., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0035551 · Cited by 62
“However, this genetic association with AMD risk has not been reproduced in recent genome wide association and case-control studies [32–34].”
BackgroundInfluentialMuqit, M. M. K. (2010) · Archives of Ophthalmology · doi:10.1001/archophthalmol.2010.36 · Cited by 58
“Ultrashort pulse-duration photocoagulation in Macaca retina has demonstrated that the RPE may elevate and detach from the Bruch membrane.4 Fourier domain OCT demonstrated that laser photocoagulation effects on the tissue were localized to the JI/OSP and the apical RPE.”
BackgroundInfluentialGrunin, M. A., Burstyn‐Cohen, T., Hagbi-Levi, S., Peled, A., & Chowers, I. (2012) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.11-9165 · Cited by 58
Usui, Y., Westenskow, P. D., Murinello, S., Dorrell, M. I., Scheppke, L., Bucher, F., Sakimoto, S., Paris, L. P., Aguilar, E., & Friedlander, M. (2015) · Annual Review of Vision Science · doi:10.1146/annurev-vision-082114-035439 · Cited by 59
Persistent inflammatory state after photoreceptor loss in an animal model of retinal degeneration
Noailles, A., Maneu, V., Campello, L., Gómez‐Vicente, V., Lax, P., & Cuenca, N. (2016) · Scientific Reports · doi:10.1038/srep33356 · Cited by 59
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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