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Feeling Yu Ting Chen, Delu Zhou, Todd Metzger, Mark Anderson, Nancy McNamara; CCR2-expressing bone marrow derived cells promote retinal inflammation in a mouse model of uveitis. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1789.
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Treatment of autoimmune eye disease is an ongoing challenge in ophthalmology. The current clinical therapeutic approach relies on general suppression of the immune system and there is an urgent need for more specific treatments with fewer side effects. Mice deficient in the autoimmune regulator (aire) gene develop a spontaneous, CD4+ T cell-mediated, autoimmune uveitis that mimics endogenous uveitis in humans. While the role of T cells in human uveitis is evident through the therapeutic effect of cyclosporin A, the underlying pathogenesis is not fully understood and the immune mediators linking CD4+ T cells to retinal inflammation are largely unknown. We investigated the role of CC chemokine receptor 2 (CCR2)-expressing microglial cells in promoting the recruitment of CD4+ T cells and provoking retinitis in aire knockout (KO) mice.
Retinal histology and immunostaining of CD4+ T cells and microglial cells were examined in adult wild type, aire KO, and aire/ccr2 KO mice. Bone marrow chimera mice were generated to elucidate the contribution and functional relevance of CCR2 to immune cell infiltration, retinal inflammation and damage to the neuroretinal tissue.
We observed intense infiltration of CD4+ T cells and microglial cells throughout the retina and choroid of aire KO mice. Infiltration was accompanied by extensive neuroretinal cell death and photoreceptor loss. Conversely, we observed significantly reduced numbers of infiltrating CD4+ T cells and F4/80+ macrophages in the retinas of aire/ccr2 KO mice. With reduced inflammation, we noted significant improvements in neuroretinal integrity and preservation of the photoreceptors. Moreover, through the reconstitution of aire KO mice with ccr2 KO bone marrow-derived cells we were able to reduce immune cell infiltration and largely restore the retinal phenotype
CCR2-dependent migration of bone marrow-derived cells is a major contributor to retinal damage in aire KO mice with autoimmune uveitis. Signaling via CCR2 was required for the efficient recruitment of autoreactive CD4+ T cells to the retina. Accordingly, loss of CCR2 effectively rescued the neuroretina from destruction. These data suggest a novel approach for treating autoimmune retinitis that includes the inhibition of CCR2 signaling.
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