Omega-3 Polyunsaturated Fatty Acids Alleviate Retinal Lesion of Ccl2/cx3cr1 Deficient Mice

Abstract

Purpose: : Ccl2/Cx3cr1 deficient mice (Ccl2^-/-/Cx3cr1^-/-) develop a broad-spectrum pathology of age-related macular degeneration (AMD). Epidemiological studies have documented that omega-3 long chain polyunsaturated fatty acid (N3) diet lowers the risk of AMD development. This study is to test if N3 feeding would alleviate the retinal lesions of Ccl2^-/-/Cx3cr1^-/-.

Methods: : Breeding pairs of Ccl2^-/-/Cx3cr1^-/- and wild types were divided into two groups and fed with high or low N3 diet starting from preconception, respectively. Their pups were counted as experiment subjects and continued in the same diet until 8 months old. Funduscopy, histopathology, retinal A2E (a major lipofuscin fluorophore that accumulated during AMD) quantification were conducted. Serum and ocular N3/N6 ratio, reactive N3 metabolites (leukotriene B4, resolvins, protectins etc), and AMD-related gene expression (complement factors, ERp29 etc) were measured and compared between the two groups.

Results: : N3/N6 in serum and ocular tissues were much higher in Ccl2^-/-/Cx3cr1^-/- ingested with high N3 than low N3 diet. Although similar retinal lesions including drusen, retinal pigment epithelial abnormalities, and photoreceptor degeneration were observed at 4-6 wks of age in both groups, the number of lesions was decreased in the mice that ingested a high N3 diet from 3-8 months of age. In contrast, in the mice that ingested the low N3 diet, the retinal lesions continued to progress. A2E was significantly lower in the retina of the high N3 as compared to that of the low N3 group. We observed the altered profiles of AMD-related molecules and reactive N3 metabolites after different treatments. Wild-type did not develop any retinal lesions on either high or low N3 chow.

Conclusions: : Our data show that N3 ameliorated the progression of retinal lesions in Ccl2^-/-/Cx3cr1^-/-. The likely cause for this observation is the enriched docosahexaenoic acid (DHA) intake in the mice fed with the high N3 diet. DHA is shown to promote RPE cell survival by being the precursor of a series of biological reactive metabolites, which could be of anti-inflammation and neuroprotection. The data also support the epidemiological studies of N3 in slowing down the progression of AMD. Furthermore, Ccl2^-/-/Cx3cr1^-/- can be used to screen various therapeutic agents for AMD.

Keywords: age-related macular degeneration • nutritional factors • pathology: experimental