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Anat London, Elena Itskovich, Inbal Benhar, Matthias Mack, Steffen Jung, Michal Schwartz; 'Healing' Monocyte-Derived Macrophages are Required for Retinal Ganglion Cell Survival and Progenitor Cell Renewal in the Injured Mammalian Retina: Implications to Glaucoma. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3938.
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© ARVO (1962-2015); The Authors (2016-present)
Retinal ganglion cell (RGC) death is a hallmark of many retinal neuropathies. Neuroprotection and cell renewal are vital for the integrity of the visual system following insult, yet are limited in the adult mammalian retina. As healing in peripheral tissues is highly dependent on blood-derived macrophages, we tested whether these cells are also required following an insult to the visual system.
Adult mice were subjected to retinal insult in models of glutamate intoxication and increased intraocular pressure. RGC survival, renewal of retinal progenitor cells (RPCs), the recruitment of distinct myeloid populations and their contribution to the local retinal milieu were analyzed by retrograde labeling of RGCs, immunohistochemistry, flow-cytometry and quantitative Real Time PCR. Bone-marrow chimeras were used to characterize these myeloid populations and specifically to identify the infiltrating monocyte-derived macrophages. Effects of monocyte depletion or augmentation were tested using the anti-CCR2 antibody, MC-21, or adoptive transfer of monocytes, respectively.
Following glutamate intoxication, monocyte-derived macrophages infiltrated the retina and localized mainly to the ganglion cell layer. Enhancement of the monocytic population augmented the numbers of proliferating RPCs and increased the survival of RGCs, whereas depletion of monocytes in the blood resulted in diminished RGC survival and RPC renewal. The monocyte-derived macrophages contributed to the immunoregulatory and neuroprotective milieu of the injured retina. They down-regulated the accumulation of other immune cells and restored immune homeostasis. The neuroprotective effect of the macrophages was dependent on their potential to produce the anti-inflammatory cytokine, interleukin-10, and to express major histocompatibility complex class II (MHC-II) molecules.
We thus attribute to infiltrating blood-derived macrophages a novel role in the resolution of local retinal inflammation, with far-reaching implications to glaucoma and other neurodegenerative disorders.
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