Early Focal Expression of the Chemokine Ccl2 by Muller Cells during Exposure to Damage-Inducing Bright Continuous Light

PURPOSE. To investigate the time course and localization of Ccl2 expression and recruitment of inflammatory cells associated with light-induced photoreceptor degeneration. METHODS. Sprague-Dawley (SD) rats were exposed to 1000 lux light for up to 24 hours, after which some animals were allowed to recover in dim light (5 lux) for 3 or 7 days. During and after exposure to light, the animals were euthanatized and the retinas processed. Ccl2 expression was assessed by qPCR, immunohistochemistry, and in situ hybridization at each time point. Counts were made of perivascular monocytes/microglia immunolabeled with ED1, and photoreceptor apoptosis was assessed with TUNEL. RESULTS. Upregulation of Ccl2 expression was evident in the retina by 12 hours of exposure and correlated with increased photoreceptor death. Ccl2 expression reached its maximum at 24 hours, coinciding with peak cell death. Immunohistochemistry and in situ hybridization showed that Ccl2 is expressed by Muller cells from 12 hours of exposure, most intensely in the superior retina, in the region of the incipient light-induced lesion. After the Muller cell-driven expression of Ccl2, there was a substantial recruitment of monocytes to the local retina and choroidal vasculature. This coincided spatially with the expression of Ccl2 in the superior retina. Peak monocyte infiltration followed maximum Ccl2 expression by up to 3 days. Furthermore, Ccl2 immunoreactivity was observed in many infiltrating monocytes after a 24-hour exposure. CONCLUSIONS. The data indicate that photoreceptor death promotes region-specific expression of Ccl2 by Muller cells, which facilitates targeting of monocytes to sites of injury. The data suggest that recruitment of monocytes to developing lesions is secondary to signaling events in the retina. (Invest Ophthalmol Vis Sci. 2011;52:2379-2388) DOI: 10.1167/iovs.10-6010