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Joseph C Besharse, Janet R Sparrow, Joseph Fogerty, Peter J Volberding; Massive Recruitment of Subretinal Macrophages in Mfrp Deficient Mice Does Not Impact Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3534.
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© ARVO (1962-2015); The Authors (2016-present)
Deficiency in MFRP, a type 2 membrane protein of the RPE, results in photoreceptor degeneration accompanied by extensive accumulation of macrophages/microglia in the subretinal space. Studies using bone marrow chimeras with YFP donor mice indicates that the subretinal cells in MFRP deficient mice are blood-derived macrophages. Since accumulation of macrophages/microglia in other retinal degeneration models reportedly enhances or exacerbates photoreceptor pathology, we set out to determine the role of these cells in MFRP mutant mice by reducing their entry into the subretinal space.
Ccl2 and its receptor Ccr2 are often involved in the recruitment of monocytic cells into tissues. Consequently, we studied MFRP deficient mice on a Ccl2-/- genetic background. We also conducted bone marrow transplants on MFRP using donor mice in which red fluorescent protein (RFP) replaced the coding sequence of Ccr2. Loss of photoreceptors was monitored at 3 and 5 months by measuring outer nuclear layer (ONL) thickness and the number of macrophages/microglia in the subretinal space and retina was monitored using IBA1, a marker for both macrophages and microglia.
Loss of Ccl2 had no impact on either recruitment of subretinal cells or retinal degeneration in MFRP deficient mice. The double mutants exhibited the same degree of photoreceptor loss as MFRP mutant mice and the same number of subretinal macrophages and retinal microglia at both 3 and 5 months of age. In contrast, MFRP deficient mice that received whole body irradiation followed by bone marrow transplants from donors lacking CCR2 exhibited a substantial depletion of subretinal IBA1+ cells without altering the number of IBA1+ cells in the retina (microglia). Despite a substantial depletion of subretinal macrophages, this treatment had no impact on ONL thickness at 3 or 5 months of age.
Massive accumulation of subretinal macrophages in MFRP deficient mice does not cause or exacerbate photoreceptor degeneration during the major phase of photoreceptor degeneration. These findings suggest that the massive accumulation of subretinal macrophages is a secondary consequence rather than a cause of overt pathology.
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