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Scott J. Robbie, Ulrich F. Luhmann, Barker E. Susie, Yanai Duran, Alexander J. Smith, Robin R. Ali, James W. Bainbridge; Increased Severity Of Choroidal Neovascularisation With Age Is Associated With Enhanced CCL2-mediated Recruitment Of Neutrophils. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1669.
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Laser-induced choroidal neovascularisation (CNV) is more severe in older mice. The mechanism for this is unknown. The purpose of this work was to determine whether upregulation of the chemokine CCL2 in the choroid with age results in the enhanced recruitment of pro-angiogenic inflammatory cells that mediate CNV severity.
Using 6-colour flow cytometry, we established the proportions of resident innate immune cells in the retinae and choroids of wild-type (WT) and CCL2-/- mice and the changes in these populations with increasing age. The effects of these aging changes on CNV lesion size in WT and CCL2-/- mice were then determined using the laser model. We conducted serial fluorescein angiography to determine differences in the rate of development of CNV between young and old WT animals. We then induced CNV in <4 month, 12 month and 24 month old WT and CCL2-/- mice and analysed innate immune cells in retinal and choroidal tissue by flow cytometry at 3 days post-laser, normalising to age-matched non-injured tissue.
We observed increases over time in CD11b+ Gr-1Low/Mid F4/80High CD11cMid cell populations (likely activated macrophages) in the uninjured retinae and choroids of both WT and CCL2-/- mice from an early age. Increases in the choroid appear to precede those in the retina. CNV lesion size increased with age in both WT and CCL2-/- animals but was consistently reduced in the latter. The effect of aging on CNV severity appeared attenuated in CCL2-/- animals. Whilst CNV lesion size stabilises at 3 days post-induction in young animals, lesion growth continues up to 7d in old WT mice. Analysis of tissue obtained at 3d post-CNV reveals more neutrophils in the choroids of old WT animals and this effect is attenuated in CCL2-/- animals. Induction of CNV results in the emigration of macrophages from the retinae and choroids of both genotypes.
We found no evidence that increased CNV lesion size is associated with the proportions of macrophages in uninjured retina and choroid. However, the enhanced recruitment of neutrophils, partly mediated by CCL2, may account for the increase in CNV lesion size observed with age.
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