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Hongkang Xi, Tom Truong, Justin Elstrott, Jianhua Tao, Monika Dohse, Rommel Arceo, Lauri Diehl, Abdoulaye Sene, Menno Van Lookeren Campagne; Inflammatory monocytes but not microglia contribute to light-induced retinal degeneration. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5551.
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Activated resident microglia and infiltrating blood monocyte-derived macrophages have been implicated in several pre-clinical models of retinal degeneration. However, the relative contribution of microglia and circulating monocyte-derived macrophages in retinal inflammation are not well understood. Here we determined the contribution of inflammatory monocytes versus microglia to photoreceptor loss in an experimental model of light-induced retinal degeneration.
To deplete blood monocytes, male Balb/c mice were treated systemically with either clodronate-containing liposomes (1 mg i.v. daily starting 2 days before light exposure) or with IL34 and CSF1 neutralizing antibodies (200 μg i.p. three times per week starting 2 weeks before light exposure). Microglia depletion was achieved by feeding the male Balb/c mice with a CSF1R small molecule inhibitor (PLX3397, 290 mg/kg chow) for 21 days. The mice were exposed to fluorescent light (1200 lux) for 7 days while treated with depleting agents. Retinal degeneration was assessed by Spectral Domain Optical Coherence Tomography (SD-OCT) and flow cytometry. Blood monocytes and retinal microglia were quantified by flow cytometry and immunohistochemistry.
Systemic treatment with clodronate or combined IL34 and CSF1 neutralizing antibodies depleted blood inflammatory (Ly6Chi) monocytes by over 90% while retinal microglia numbers were not affected. Peripheral blood monocyte depletion with anti-IL34 and anti-CSF1 resulted in abrogation of Iba1+ myeloid cell accumulation in the subretinal space and choroidal capillary in mice exposed to light. Light-induced photoreceptor degeneration was significantly decreased in monocyte-depleted mice compared to control mice. Microglia numbers in the retina were reduced by over 90% in Balb/c mice treated with PLX3397 for 21 days while peripheral blood Ly6Chi monocyte numbers remained unaffected. Surprisingly, microglia-depleted mice exhibited a similar degree of photoreceptor degeneration as the control mice upon light exposure.
Our results indicate that peripheral blood inflammatory monocytes but not resident microglia contribute to phototoxicity-induced retinal degeneration in mice, positioning circulating monocytes as a potential target for therapeutic intervention in retinal diseases.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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