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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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ResultInfluentialWill-Orrego, A., Qiu, Y., Fassbender, E. S., Shen, S., Aranda, J., Kotagiri, N., Maker, M., Liao, S.-M., JAFFEE, B. D., & Poor, S. H. (2018) · Journal of Ocular Pharmacology and Therapeutics · doi:10.1089/jop.2017.0131 · Cited by 6
Zhu, Q., Zeng, D.-K., & Li, F. (2020) · Minerva Endocrinology · doi:10.23736/s0391-1977.19.02964-x · Cited by 6
Chen, J., Lu, T., Chen, C., Zheng, W., Lü, L., & Li, N. (2024) · European journal of medical research · doi:10.1186/s40001-024-02163-1 · Cited by 6
The role of microglia in glaucoma - trigger and potential target
Chen, L., Yang, S., Wang, D., & Huang, P. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1685495 · Cited by 6
Die Rolle des Glaskörpers in der Pathogenese der exsudativen altersabhängigen Makuladegeneration
Boneva, S., Haritoglou, C., Schultheiß, M., Binder, S., & Sebag, J. (2023) · Die Ophthalmologie · doi:10.1007/s00347-023-01934-1 · Cited by 5
Tarallo, V., Trotta, S. M., Panico, S., D’Orsi, L., Mercadante, G., Cicatiello, V., & Falco, S. D. (2024) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.65.8.12 · Cited by 5
“For a long time, macrophage-derived VEGF-A was believed to be an important factor for inflammation-driven angiogenesis in CNV. 29,30 However, a recent study using several myeloid-specific VEGF-A KO models has shown that myeloid-derived VEGF-A production does not contribute significantly to CNV and vascular leakage.”
BackgroundInfluentialLuo, Y., Liu, J., Feng, W., Lin, D., Chen, M., & Zheng, H. (2024) · Evolutionary Bioinformatics · doi:10.1177/11769343241272413 · Cited by 5
Aberrant lipid accumulation and retinal pigment epithelium dysfunction in PRCD-deficient mice
Motipally, S. I., Kolson, D. R., Guan, T., & Kolandaivelu, S. (2024) · Experimental Eye Research · doi:10.1016/j.exer.2024.110016 · Cited by 5
Seol, A., Kim, J., Jin, Y.-J., Song, H.-J., Roh, Y.-J., Kim, T.-R., Park, E.-S., Park, K.-H., Park, S., Uddin, M. S., et al. (2024) · Pharmaceuticals · doi:10.3390/ph17091193 · Cited by 7
Altered Cholesterol Homeostasis in Aged Macrophages Linked to Neovascular Macular Degeneration
Chen, J., & Smith, L. E. H. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.03.010 · Cited by 5
“Previous studies have focused on the chemotaxis and drusen-derived activation of inflammatory cells in AMD (Combadière et al., 2007; Doyle et al., 2012).”
Basic Mechanisms of Pathological Retinal and Choroidal Angiogenesis
Vavvas, D. G., & Miller, J. W. (2012) · Elsevier eBooks · doi:10.1016/b978-1-4557-0737-9.00026-6 · Cited by 5
Behnke, V., & Langmann, T. (2020) · Biochemistry and Biophysics Reports · doi:10.1016/j.bbrep.2020.100866 · Cited by 5
Macrophages in age-related macular degeneration: a narrative review
Khademi, S., Yu, Z., Zhou, T., Song, B., & Xu, Z. (2024) · Aging advances. · doi:10.4103/agingadv.agingadv-d-24-00007 · Cited by 5
Chemokines and chemokine receptors in the nervous system
Trettel, F., Angelantonio, S. D., Limatola, C., & Ransohoff, R. M. (2008) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2008.04.006 · Cited by 5
“Retina Homeostasis of the aging retina (Combadière et al., 2007)”
BackgroundInflammation in age-related macular degeneration: pathological or physiological?
Yasukawa, T. (2009) · Expert Review of Ophthalmology · doi:10.1586/eop.09.1 · Cited by 5
Woodward, D. F., Wang, J. W., Ni, M., Bauer, A. J., & Poloso, N. J. (2018) · Journal of Ocular Pharmacology and Therapeutics · doi:10.1089/jop.2018.0077 · Cited by 4
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Choroidal macrophages in homeostasis, aging and age-related macular degeneration
Khan, A. H., & Mulfaul, K. (2024) · Experimental Eye Research · doi:10.1016/j.exer.2024.110159 · Cited by 4
Genetics in Age-Related Macular Degeneration
Broadhead, G., Chang, A., & McCluskey, P. (2012) · Asia-Pacific Journal of Ophthalmology · doi:10.1097/apo.0b013e31826e1d4a · Cited by 4
Inhibition of Experimental Age-Related Macular Degeneration by ZQMT in Mice
Yang, L., Meng, H., Luo, D., Deng, T., Li, M., Zou, B., Ge, X., Hu, X., Liu, Y., Li, X., et al. (2019) · Current Molecular Medicine · doi:10.2174/1566524019666190425195706 · Cited by 4
Tear and serum interleukin-8 and serum CX3CL1, CCL2 and CCL5 in sulfur mustard eye-exposed patients
Ghazanfari, T., Ghasemi, H., Yaraee, R., Mahmoudi, M., Javadi, M. A., Soroush, M. R., Faghihzadeh, S., Majd, A. M. M., Shakeri, R., Babaei, M., et al. (2019) · International Immunopharmacology · doi:10.1016/j.intimp.2019.105844 · Cited by 4
Recombinant sulfated CCR2 peptide trap reduces retinal degeneration in mice
Jung, S., Jin, S., Chae, J., Jo, G., Chung, H., Lyu, J., & Lee, J. (2021) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2021.08.002 · Cited by 4
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Li, D., Peng, X., & Sun, H. (2015) · Canadian Journal of Ophthalmology · doi:10.1016/j.jcjo.2015.08.010 · Cited by 4
Age-related macular degeneration in patients with uveitis
Fox, A. R., Chew, E. Y., MEYERLE, C. B., Vitale, S., Ferris, F. L., Nussenblatt, R. B., & Sen, H. N. (2016) · British Journal of Ophthalmology · doi:10.1136/bjophthalmol-2016-308587 · Cited by 4
Rodent Models of Retinal Degeneration: From Purified Cells in Culture to Living AnimalsPreprint
Fradot, V., Augustin, S., Fontaine, V. K., Marazova, K., Guillonneau, X., Sahel, J., & Picaud, S. A. (2023) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a041311 · Cited by 4
C3aR1-Deletion Delays Retinal Degeneration in a White-Light Damage Mouse Model
Behnke, V., Wolf, A., Hector, M., & Langmann, T. (2025) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.66.1.15 · Cited by 3
“14 In 17–19 AMD is a major blinding disease in the elderly of the western world, with the number of affected people rising rapidly.”
Wada, I., Nakao, S., Shiose, S., Kaizu, Y., Yamaguchi, M., Ishikawa, K., Kiyohara, K., Ishibashi, T., & Sonoda, K. (2025) · Japanese Journal of Ophthalmology · doi:10.1007/s10384-025-01219-x · Cited by 3
“Under normal physiological conditions, microglia reside around retinal blood vessels [28, 29], but in inflammatory diseases like nAMD, they become activated and infiltrate the retina [30].”
Yan, C., Figueiredo, C. A., Pompös, I.-M., Ugursu, B., Arribas-Lange, P., Skosyrski, S., Yang, S., Althoff, P., Kociok, N., Joussen, A. M., et al. (2025) · Journal of Neuroinflammation · doi:10.1186/s12974-025-03508-1 · Cited by 3
“Retinal microglia have been negatively related to AMD pathology, as their accumulation in sites of retinal degradation accelerates drusen body formation, photoreceptor degeneration, and pathological neovascularization [38–40].”
Dialogue Between the Clock Gene Bmal1 and Retinopathy: What Is the Exact Relationship?
Cui, Y., Li, H., Fan, W., Wu, H., Wang, J., Qu, C., Pu, N., & Tao, Y. (2025) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.70490 · Cited by 3
“This participation is characterized by the expression of numerous inflammatory markers, the release of proinflammatory cytokines (such as TNF-α, IL-1β, MCP-1), and the subsequent amplification of inflammatory cascade responses following activation [48–50].”
Inner-retinal changes in AMD: Evidence, mechanisms, and future perspectives
Trinh, M., Kalloniatis, M., Jones, B. W., Yiu, G. C., Borrelli, E., & Nivison‐Smith, L. (2026) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2026.101463 · Cited by 3
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Rôles des chimiokines dans le développement de la dégénérescence maculaire liée à l’âge
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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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