title: Ccl2, Cx3cr1 and Ccl2/Cx3cr1 chemokine deficiencies are not sufficient to cause age-related retinal degeneration.
abstract: Monocytes, macrophages, dendritic cells and microglia play critical roles in the local immune response to acute and chronic tissue injury and have been implicated in the pathogenesis of age-related macular degeneration. Defects in Ccl2-Ccr2 and Cx3cl1-Cx3cr1 chemokine signalling cause enhanced accumulation of bloated subretinal microglia/macrophages in senescent mice and this phenomenon is reported to result in the acceleration of age-related retinal degeneration. The purpose of this study was to determine whether defects in CCL2-CCR2 and CX3CL1-CX3CR1 signalling pathways, alone or in combination, cause age-dependent retinal degeneration. We tested whether three chemokine knockout mouse lines, Ccl2(-/-), Cx3cr1(-/-) and Ccl2(-/-)/Cx3cr1(-/-), in comparison to age-matched C57Bl/6 control mice show differences in subretinal macrophage accumulation and loss of adjacent photoreceptor cells at 12-14 months of age. All mouse lines are derived from common parental strains and do not carry the homozygous rd8 mutation in the Crb1 gene that has been a major confounding factor in previous reports. We quantified subretinal macrophages by counting autofluorescent lesions in fundus images obtained by scanning laser ophthalmoscopy (AF-SLO) and by immunohistochemistry for Iba1 positive cells. The accumulation of subretinal macrophages was enhanced in Ccl2(-/-), but not in Cx3cr1(-/-) or Ccl2(-/-)/Cx3cr1(-/-) mice. We identified no evidence of retinal degeneration in any of these mouse lines by TUNEL staining or semithin histology. In conclusion, CCL2-CCR2 and/or CX3CL1-CX3CR1 signalling defects may differentially affect the trafficking of microglia and macrophages in the retina during ageing, but do not appear to cause age-related retinal degeneration in mice.
authors.affiliation: Department of Genetics, UCL Institute of Ophthalmology, 11-43 Bath Street, EC1V9EL London, United Kingdom. u.luhmann@ucl.ac.uk
authors.forename: Ulrich F O
authors.initials: UF
authors.lastname: Luhmann
authors.forename: Livia S
authors.initials: LS
authors.lastname: Carvalho
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Robbie
authors.forename: Jill A
authors.initials: JA
authors.lastname: Cowing
authors.forename: Yanai
authors.initials: Y
authors.lastname: Duran
authors.forename: Peter M G
authors.initials: PM
authors.lastname: Munro
authors.forename: James W B
authors.initials: JW
authors.lastname: Bainbridge
authors.forename: Robin R
authors.initials: RR
authors.lastname: Ali
mesh_terms: D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002452:Cell Count; D018932:Chemokine CCL2 / Q000502:physiology*; D005838:Genotype; D020287:In Situ Nick-End Labeling; D008264:Macrophages / Q000378:metabolism; D008268:Macular Degeneration / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D009887:Ophthalmoscopy; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction; D019707:Receptors, Chemokine / Q000502:physiology*
chemical_list: C491049:Aif1 protein, mouse; D000073883:CX3C Chemokine Receptor 1; D002135:Calcium-Binding Proteins; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C471885:Cx3cr1 protein, mouse; D008840:Microfilament Proteins; D019707:Receptors, Chemokine