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Liliana Guedez, Nicholas Popp, Chi-Chao Chan; The role of chemokine CCL-2 and CX3CR1 in inflammatory-related retinal degeneration. Invest. Ophthalmol. Vis. Sci. 2016;57(12):4507.
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© ARVO (1962-2015); The Authors (2016-present)
Inflammation is reported as a major cause of retinal degeneration, implicated in the pathogenesis of degenerative retinal diseases such as age-related macular degeneration(AMD). Identification of inflammation targets and mechanisms is of interest for the development of effective therapies.Chemokines mediate inflammation of the retina by modulating macrophage and microglia activation. A recent report showed that antibiotic treatment can promote inflammation through the translocation of bacteria via CX3CR1 in dendritic cells. In this study, we investigated the role of chemokine CCL-2 and CX3CR1 in retinal degeneration.
Six-week old Ccl2/Cx3cr1 deficient (DKO) mice (Tuo, 2007) were treated or untreated with broad spectrum antibiotics (N=10 each) as previously reported (Guedez, ARVO 2015). Eyes from DKO mice and wild-type controls were enucleated and processed for routine histology and immunohistochemistry analysis. RNA was extracted and differential gene expression was analyzed in triplicate in a custom-made RT-PCR array. Pathway analysis of significantly deregulated genes was performed using Genomatix.
Histology analysis of eyes from untreated DKO mice demonstrated focal atrophy and degeneration of photoreceptors as compared with wild-type control eyes. In contrast to the untreated DKO mice, the antibiotic-treated DKO mice eyes showed a more severe retinal degeneration, including thinning or focal loss of photoreceptors (outer nuclear layer, inner and outer segments). Signs of choroidal neovascularization were also found in the antibiotic-treated mice. Furthermore, antibiotic-treated eyes demonstrated significant upregulation of transcripts for Il-6, Ifng, Timp3, Cfh, Nfkb1, Apoe, Icam1, Casp8, Tnfa, Nos2, and downregulation of Sod2, Sod1 and Cxcl2. Further analysis of genes affected by Ccl2/Cx3cr1 deficiency in antibiotic-treated mice revealed their interaction in inflammatory pathways controlled by IL-6, TNF-α, and IFN-γ.
This study strongly supports a role for chemokines in retinal degeneration. Ccl2/Cx3cr1 deficiency affects inflammation pathways associated with key pathological aspects of focal photoreceptor and RPE degeneration in AMD. Antibiotic treatment severely worsened retina degeneration, and upregulated factors implicated in the progression of AMD. This study identifies inflammation targets with therapeutic potential in the treatment of AMD.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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