期刊
EXPERIMENTAL EYE RESEARCH
卷 86, 期 4, 页码 675-683出版社
ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD
DOI: 10.1016/j.exer.2008.01.014
关键词
age-related macular degeneration; animal model; chemokine; cytokine; complement factor; toll-like receptor 4; microglia; macrophage
资金
- Intramural NIH HHS [Z01 EY000418-04, Z01 EY000222-22] Funding Source: Medline
Age-related macular degeneration (AMD) is the leading cause of blindness in the United States. Cel2 knock-out (KO) mice sporadically develop the cardinal features of AMD in their senescent stage. Humans bearing a loss of function variant or single nucleotide polymorphism (SNP) in CX3CR1 are at increased risk of developing AMD. We recently developed Ccl2(-/-)/Cx3cr(-/-) mice, which consistently develop retinal degeneration with many AMD features. Since there is strong evidence for an immunological role in AMD pathogenesis, we examined ocular immune protein expression levels in Ccl2(-/-)/Cx3cr1(-/-), Ccl2(-/-), Cx3crl(-/-), and age-matched wild-type (WT) mice. Immunohistochemistry revealed increased complement C3d in Bruch's membrane, retinal pigment epithelium (RPE), choroidal capillaries, and particularly drusen of the Ccl2(-/-) Cx3cr1(-/-) mice relative to the WT controls. No change was detected in single KO mice. Real-time RT-PCR revealed a 2.5-fold increase in C3 expression in the Ccl2(-/-)/Cx3cl(-/-). While the retinas of four month old WT and Ccl2(-/-) showed minimal immunoreactivity for markers of macrophages and microglia, infiltrates of these mononuclear phagocytic cells were detected in the Ccl2(-/-)/Cx3cr(-/-) retinal lesions and a few foci in the Cx3c1(-/-) retina. The Ccl2(-/-)/Cx3cr1(-/-) had reduced toll-like receptor 4 (TLR4) expression in the RPE. Following LPS injection, the Ccl2(-/-)/Cx3cr1(-/-) had significantly reduced endotoxin-induced uveitis scores and showed a diminished increase in Tlr4 mRNA expression. No changes in TLR4 expression were detected in either single KO. Autoantibodies against the retina and photoreceptors were also detected in the Ccl2(-/-) /Cx3cr1(-/-) serum. Real-time RT-PCR revealed significant increases in Ccl5 transcript in the Ccl2(-/-)/Cx3cr1(-/-) relative to the WT. These results suggest that innate immunity and possibly adaptive immunity play an important role in Ccl2(-/-)/Cx3cr1(-/-) retinal degeneration. Moreover, since human AMD patients show similar immunopathological profiles, these results support the Ccl2(-/-)/Cx3Cr1(-/-) as a suitable model for human AMD. Published by Elsevier Ltd.
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