Chen YuTing Feeling, Zhou Delu, Metzger Todd, Gallup Marianne, Jeanne Marion, Gould Douglas B, Anderson Mark S, McNamara Nancy A
Francis I. Proctor Foundation, University of California, San Francisco, California.
Diabetes Center, University of California, San Francisco, California.
Am J Pathol. 2014 Jun;184(6):1695-705. doi: 10.1016/j.ajpath.2014.02.024. Epub 2014 Apr 13.
Development of novel strategies to treat noninfectious posterior uveitis is an ongoing challenge, in part because of limited availability of animal models that mimic the naturally occurring disease in humans. Mice deficient in the autoimmune regulatory gene Aire develop a spontaneous T-cell and macrophage-mediated autoimmune uveitis that closely recapitulates human endogenous uveitis and thus provide a useful model for mechanistic and therapeutic investigations. Lymphocytic and mononuclear infiltration of the retina in Aire knockout (KO) mice triggers the onset of uveitis from initial retinal inflammation to eventual destruction of the neuroretina with loss of photoreceptors. The C-C chemokine receptor type 2 protein (CCR2) functions in directing monocyte and macrophage migration to inflamed tissues via interaction with monocyte chemotactic proteins. Using the Aire KO mouse model, we demonstrated an essential role for CCR2 in the pathogenesis of autoimmune-mediated uveitis. Loss of functional CCR2 effectively reduced immune cell infiltration and rescued the retina from destruction. CCR2-dependent migration of bone marrow-derived cells provided the driving force for retinal inflammation, with CCR2-expressing mononuclear cells contributing to retinal damage via recruitment of CD4(+) T cells. These studies identify the CCR2 pathway as a promising therapeutic target that may prove an effective approach to treat uveitis associated with autoimmunity.
开发治疗非感染性后葡萄膜炎的新策略一直是一项挑战，部分原因是缺乏能模拟人类自然发生疾病的动物模型。自身免疫调节基因Aire缺陷的小鼠会发生自发性T细胞和巨噬细胞介导的自身免疫性葡萄膜炎，这与人类内源性葡萄膜炎非常相似，因此为机制和治疗研究提供了一个有用的模型。Aire基因敲除（KO）小鼠视网膜中的淋巴细胞和单核细胞浸润引发了葡萄膜炎的发作，从最初的视网膜炎症到最终神经视网膜的破坏以及光感受器的丧失。C-C趋化因子受体2蛋白（CCR2）通过与单核细胞趋化蛋白相互作用，在引导单核细胞和巨噬细胞迁移到炎症组织中发挥作用。利用Aire KO小鼠模型，我们证明了CCR2在自身免疫介导的葡萄膜炎发病机制中起关键作用。功能性CCR2的缺失有效地减少了免疫细胞浸润，并使视网膜免于破坏。骨髓来源细胞的CCR2依赖性迁移为视网膜炎症提供了驱动力，表达CCR2的单核细胞通过招募CD4(+) T细胞导致视网膜损伤。这些研究确定CCR2途径是一个有前景的治疗靶点，可能是治疗与自身免疫相关的葡萄膜炎的有效方法。
