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.
Highlights
IntroductionMonocytes circulate between the bone marrow, blood and spleen and consist of several phenotypic and functional subsets (Geissmann et al, 2003)
Monocytes, macrophages, dendritic cells, and microglia are key regulator and effector cells of the immune system and have specific roles in immune surveillance and maintenance of tissue homeostasis (Geissmann et al, 2010).Monocytes circulate between the bone marrow, blood and spleen and consist of several phenotypic and functional subsets (Geissmann et al, 2003)
In a recent study of CCDKO (Ccl2À/À/Cx3cr1À/À) mice that were backcrossed to generate re-derived, closely related Ccl2À/À, Cx3cr1À/À and Ccl2À/À/Cx3cr1À/À mouse lines, we identified the rd8 mutation in the Crb1 gene as a dominant confounding factor that was responsible for the early onset retinal degeneration previously attributed to the combined deficiency of CCchemokine ligand 2 (Ccl2) and Cx3cr1 in CCDKO mice (Luhmann et al, 2012; Tuo et al, 2007)
Summary
Monocytes circulate between the bone marrow, blood and spleen and consist of several phenotypic and functional subsets (Geissmann et al, 2003) These monocyte subsets can be distinguished by the expression pattern of chemokine surface receptors and adhesion molecules, that include CD14, CD16 and CD64 (in human) and CD115, CD11b, Gr1/Ly6C (in mouse) as well as the CeC chemokine receptor 2 (CCR2) and fractalkine receptor CX3CR1 These molecules determine a particular mode of trafficking and functional behaviour of the respective subsets (Geissmann et al, 2003; Jung et al, 2000). In contrast “resting”/nonclassical monocytes, which express high levels of Cx3cr, but not CCR2 (human: CD14lo, CD16þCD64À; mouse: CD11bþ, Ly6Clow), patrol non-inflamed tissue and may be involved in the resolution of inflammatory processes (Auffray et al, 2007; Geissmann et al, 2003; Nahrendorf et al, 2007; Tacke and Randolph, 2006; Yona and Jung, 2010)
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