title: CCL3 production by microglial cells modulates disease severity in murine models of retinal degeneration.
abstract: 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.
authors.affiliation: Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106;
authors.forename: Hideo
authors.initials: H
authors.lastname: Kohno
authors.forename: Tadao
authors.initials: T
authors.lastname: Maeda
authors.forename: Lindsay
authors.initials: L
authors.lastname: Perusek
authors.forename: Eric
authors.initials: E
authors.lastname: Pearlman
authors.forename: Akiko
authors.initials: A
authors.lastname: Maeda
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000172:deficiency; D000429:Alcohol Oxidoreductases / Q000172:deficiency; D000818:Animals; D002470:Cell Survival; D054405:Chemokine CCL3 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D008027:Light; D019402:Macrophage Inflammatory Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D009000:Monocytes / Q000473:pathology; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism; D012162:Retinal Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012720:Severity of Illness Index
chemical_list: D018528:ATP-Binding Cassette Transporters; D000429:Alcohol Oxidoreductases; D054405:Chemokine CCL3; D018925:Chemokines; D018836:Inflammation Mediators; D019402:Macrophage Inflammatory Proteins; C512841:Abca4 protein, mouse; C525880:HSD17B6 protein, mouse