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De Fen Shen, Yujuan Wang, Jingsheng Tuo, Chi-Chao Chan; Macrophage Polarization in Ccl2/Cx3cr1 Double Deficient Mice. Invest. Ophthalmol. Vis. Sci. 2011;52(14):961.
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Ccl2/Cx3cr1double deficient mouse (DKO) is an animal model for age-related macular degeneration (AMD), which develops focal AMD-like retinal lesions, such as photoreceptor degeneration, elevated A2E, microglial activation, and occasional chorioretinal neovascularization with age. Previous studies show DKO possesses higher expression of inflammatory cytokines including IL-1β, IL-10, IFN-γ, and TNF-α. This study investigated the polarization of macrophage M1 and M2 associated chemokines, CXCL11 and CCL22, and expression of VEGF, VEGF-R, iNos and TNF-α, at different ages in wild type (WT) and DKO mice.
Two or three mice from each WT and DKO at age 20 days, 2, 4, 7 and 12 months were examined by weekly funduscopy before tissue collection. Both eyes, brain and liver from each mouse were measured for CXCL11, CCL22, VEGF, VEGF-R, iNos and TNF-α by quantitative RT-PCR. The mouse universal RNA was used as a reference.
Funduscopy showed multiple small retinal lesions at age of 20 days. The lesions became larger and confluent at age of 2, 4 and 7 months and flattened or scar-like atrophic at age of 7 and 12 months. The transcripts of CXCL11 and CCL22 in eyes increased with aging in both WT and DKO, but CXCL11 was significantly higher in DKO than in WT, while CCL22 was significantly lower in DKO than in WT. (Table)
The ratio of CXCL11/CCL22 was higher in DKO than in WT at each age. The same pattern of the expression was also found in brain and liver. The transcripts of VEGF, VEGF-R, iNos and TNF-αwere higher in DKO than in WT in all tissues at all ages. The rank of different expression levels was liver >eye> brain.
There are distinct polarized macrophage populations in WT and DKO with aging. The higher level of M1 associated chemokine (CXCL11) may promote secreting pro-inflammatory cytokines and cause tissue damage. While the lack of an adaptive increase of M2 associated chemokine (CCL22) in DKO may reduce the protective activity during aging, especially in DKO. Macrophage polarization may play a potential role in AMD-like pathogenesis in DKO.
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