Ccl2, Cx3cr1 and Ccl2/Cx3cr1 chemokine deficiencies are not sufficient to cause age-related retinal degeneration

Ulrich F O Luhmann, Livia S Carvalho, Scott J Robbie, Jill A Cowing, Yanai Duran, Peter M G Munro, James W B Bainbridge, Robin R Ali

Research output: Contribution to journalArticle

30 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)80-87
Number of pages8
JournalExperimental Eye Research
Volume107
DOIs
Publication statusPublished - Feb 2013
Externally publishedYes

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Retinal Degeneration
Chemokines
Macrophages
Microglia
Ophthalmoscopy
Photoreceptor Cells
In Situ Nick-End Labeling
Macular Degeneration
Knockout Mice
Dendritic Cells
Retina
Monocytes
Histology
Lasers
Immunohistochemistry
Staining and Labeling
Mutation
Wounds and Injuries
Genes

Cite this

Luhmann, Ulrich F O ; Carvalho, Livia S ; Robbie, Scott J ; Cowing, Jill A ; Duran, Yanai ; Munro, Peter M G ; Bainbridge, James W B ; Ali, Robin R. / Ccl2, Cx3cr1 and Ccl2/Cx3cr1 chemokine deficiencies are not sufficient to cause age-related retinal degeneration. In: Experimental Eye Research. 2013 ; Vol. 107. pp. 80-87.
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Ccl2, Cx3cr1 and Ccl2/Cx3cr1 chemokine deficiencies are not sufficient to cause age-related retinal degeneration. / Luhmann, Ulrich F O; Carvalho, Livia S; Robbie, Scott J; Cowing, Jill A; Duran, Yanai; Munro, Peter M G; Bainbridge, James W B; Ali, Robin R.

In: Experimental Eye Research, Vol. 107, 02.2013, p. 80-87.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Ccl2, Cx3cr1 and Ccl2/Cx3cr1 chemokine deficiencies are not sufficient to cause age-related retinal degeneration

AU - Luhmann, Ulrich F O

AU - Carvalho, Livia S

AU - Robbie, Scott J

AU - Cowing, Jill A

AU - Duran, Yanai

AU - Munro, Peter M G

AU - Bainbridge, James W B

AU - Ali, Robin R

N1 - Copyright © 2012 Elsevier Ltd. All rights reserved.

PY - 2013/2

Y1 - 2013/2

N2 - 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.

AB - 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.

KW - Animals

KW - Calcium-Binding Proteins

KW - Cell Count

KW - Chemokine CCL2

KW - Genotype

KW - In Situ Nick-End Labeling

KW - Macrophages

KW - Macular Degeneration

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Microfilament Proteins

KW - Ophthalmoscopy

KW - Photoreceptor Cells, Vertebrate

KW - Polymerase Chain Reaction

KW - Receptors, Chemokine

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1016/j.exer.2012.11.015

DO - 10.1016/j.exer.2012.11.015

M3 - Article

VL - 107

SP - 80

EP - 87

JO - Experimental Eye Research

JF - Experimental Eye Research

SN - 0014-4835

ER -