Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106;
J Immunol. 2014 Apr 15;192(8):3816-27. doi: 10.4049/jimmunol.1301738. Epub 2014 Mar 17.
Many degenerative retinal diseases illustrate retinal inflammatory changes that include infiltration of microglia and macrophages into the subretinal space. In this study, we examined the role of chemokines in the Abca4(-/-)Rdh8(-/-) mouse model of Stargardt disease and the Mertk(-/-) mouse model of retinitis pigmentosa. PCR array analysis of 84 chemokines and related molecules revealed 84.6-fold elevated expression of Ccl3 (MIP-1a) 24 h after light exposure in Abca4(-/-)Rdh8(-/-) mice. Only MIP-1 chemokines, including Ccl3 and Ccl4, displayed peak expression 24 h after light exposure, and peaked earlier than the other chemokines. Secretion of Ccl3 was documented only in microglia, whereas both microglia and retinal pigment epithelium cells produced Ccl2. Exposure of Cx3Cr1(gfp/Δ)Abca4(-/-)Rdh8(-/-) mice to intense light resulted in the appearance of Cx3Cr1GFP(+) monocytes in the subretinal space. To address the in vivo role of CCL3 in retinal degeneration, Ccl3(-/-)Abca4(-/-)Rdh8(-/-) mice and Ccl3(-/-)Mertk(-/-) mice were generated. Following intense light exposure, Ccl3(-/-)Abca4(-/-)Rdh8(-/-) mice displayed persistent retinal inflammation with appearance of Iba-1(+) cells in the subretinal space, severe photoreceptor cell death, and increased Ccl4 expression compared with Abca4(-/-)Rdh8(-/-) mice. In contrast, Ccl3(-/-)Abca4(-/-)Rdh8(-/-) mice exhibited a milder retinal inflammation and degeneration than Abca4(-/-)Rdh8(-/-) mice did in age-related chronic retinal degeneration under room light conditions. The deficiency of Ccl3 also attenuated the severity of retinal degeneration in Mertk(-/-) mice. Taken together, our results indicate that Ccl3 has an essential role in regulating the severity of retinal inflammation and degeneration in these mouse models.
许多退行性视网膜疾病表明视网膜炎症变化包括小胶质细胞和巨噬细胞浸润到视网膜下空间。在这项研究中，我们研究了趋化因子在 Stargardt 病 Abca4(-/-)Rdh8(-/-) 模型和色素性视网膜炎 Mertk(-/-) 模型中的作用。84 种趋化因子和相关分子的 PCR 阵列分析显示，Abca4(-/-)Rdh8(-/-) 小鼠在光暴露后 24 小时内 Ccl3（MIP-1a）的表达增加了 84.6 倍。只有 MIP-1 趋化因子，包括 Ccl3 和 Ccl4，在光暴露后 24 小时达到峰值，比其他趋化因子更早达到峰值。仅在小胶质细胞中检测到 Ccl3 的分泌，而小胶质细胞和视网膜色素上皮细胞都产生 Ccl2。将 Cx3Cr1(gfp/Δ)Abca4(-/-)Rdh8(-/-) 小鼠暴露于强光下，导致 Cx3Cr1GFP(+)单核细胞出现在视网膜下空间。为了研究 CCL3 在视网膜变性中的体内作用，生成了 Ccl3(-/-)Abca4(-/-)Rdh8(-/-) 小鼠和 Ccl3(-/-)Mertk(-/-) 小鼠。在强光暴露后，Ccl3(-/-)Abca4(-/-)Rdh8(-/-) 小鼠显示出持续的视网膜炎症，视网膜下空间出现 Iba-1(+)细胞，光感受器细胞死亡严重，与 Abca4(-/-)Rdh8(-/-) 小鼠相比，Ccl4 表达增加。相比之下，在年龄相关的慢性视网膜变性下，Ccl3(-/-)Abca4(-/-)Rdh8(-/-) 小鼠在室光条件下的视网膜炎症和变性比 Abca4(-/-)Rdh8(-/-) 小鼠更为轻微。Ccl3 的缺乏也减轻了 Mertk(-/-) 小鼠视网膜变性的严重程度。总之，我们的结果表明，Ccl3 在这些小鼠模型中调节视网膜炎症和变性的严重程度中起重要作用。
