A subpopulation of activated retinal macrophages selectively migrated to regions of cone photoreceptor stress, but had limited effect on cone death in a mouse model for type 2 Leber congenital amaurosis.
A subpopulation of activated retinal macrophages selectively migrated to regions of cone photoreceptor stress, but had limited effect on cone death in a mouse model for type 2 Leber congenital amaurosis.
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DOI：
10.1016/j.mcn.2017.09.002
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发表时间：
2017-12
期刊：
影响因子：
--
通讯作者：
Gregerson DS
中科院分区：
文献类型：
--
作者：
Tang PH;Pierson MJ;Heuss ND;Gregerson DS
利用转基因CD11c启动子表达绿色荧光蛋白（GFP）的小鼠对视网膜抗原呈递的研究发现，视网膜GFPhi细胞具有抗原呈递功能。随后的研究发现，这些高GFPhi细胞优先定位于视网膜损伤部位，这与它们的APC功能一致。由于对巨噬细胞在退行性中枢神经系统疾病中的作用感兴趣，我们研究了神经退行性视网膜模型中的GFPhi细胞。我们研究了Rpe65−/−敲除小鼠的视锥光受体细胞凋亡是否诱导了GFPhi细胞，探讨了它们与常驻小胶质细胞（MG）的关系，并测试了它们在视锥细胞存活中的作用。Rpe65−/−小鼠在B6/J背景下与cd11cfp小鼠杂交。CD11cGFPRpe65−/−小鼠也回交到cx3cr1yfp - creerrossadta小鼠，使CX3CR1+单核细胞可以被他莫昔芬消耗。采用免疫组织化学、共聚焦显微镜、荧光眼底镜和流式细胞术对视网膜进行分析。在CD11cGFPRpe65 - / -小鼠的感光细胞层中，GFPhi细胞数量的升高与2 ~ 4周龄时锥体死亡的高峰一致，并持续至少14个月。在最初的视锥细胞丢失后，发现视锥细胞缓慢的逐渐丢失，并在视网膜外继续保留GFPhi细胞。在Rpe65 - / -小鼠中，从第13天到第41天，从第390天到第420天，持续4周的他莫昔芬消耗GFPhi细胞和MG，促进了锥体存活率的小幅增加。我们没有发现GFPhi细胞来自循环的证据；所有数据都指向MG原点。MG和GFPhi细胞在营养不良的视网膜中分离良好；GFPhi细胞主要分布在感光细胞层，MG细胞主要分布在视网膜内。cd11cfp小鼠视网膜单个核细胞亚群中GFP的表达鉴定了一种不同的细胞群，这些细胞执行先前归因于MG的功能。虽然GFPhi细胞主导了巨噬细胞对视锥细胞死亡的反应，但它们的消融只导致视锥细胞存活的增加。鉴定、消融和分离这些细胞的能力将有助于分析这种活化的抗原呈递MG亚群。
Studies of antigen presentation in retina using mice that expressed green fluorescent protein (GFP) from a transgenic CD11c promoter found that retinal GFPhi cells possessed antigen presentation function. Subsequent studies found that these high GFPhi cells preferentially localized to sites of retinal injury, consistent with their APC function. Interest in the roles of macrophages in degenerative CNS diseases led us to study the GFPhi cells in a retinal model of neurodegeneration. We asked if apoptotic cone photoreceptor cell death in Rpe65−/− knockout mice induced the GFPhi cells, explored their relationship to resident microglia (MG), and tested their role in cone survival. Rpe65−/− mice were bred to CD11cGFP mice on the B6/J background. CD11cGFPRpe65−/− mice were also backcrossed to CX3CR1YFP-creERROSADTA mice so that CX3CR1+ mononuclear cells could be depleted by Tamoxifen. Retinas were analyzed by immunohistochemistry, confocal microscopy, fluorescence fundoscopy and flow cytometry. Elevated numbers of GFPhi cells were concentrated in photoreceptor cell layers of CD11cGFPRpe65−/− mice coinciding with the peak of cone death at 2 to 4 weeks of age, and persisted for at least 14 months. After the initial wave of cone loss, a slow progressive loss of cones was found that continued to retain GFPhi cells in the outer retina. Sustained, four-week Tamoxifen depletions of the GFPhi cells and MG in Rpe65−/− mice from day 13 to day 41, and from day 390 to day 420 promoted a small increase in cone survival. We found no evidence that the GFPhi cells were recruited from the circulation; all data pointed to a MG origin. MG and GFPhi cells were well segregated in the dystrophic retina; GFPhi cells were foremost in the photoreceptor cell layer, while MG were concentrated in the inner retina. The expression of GFP on a subset of retinal mononuclear cells in CD11cGFP mice identifies a distinct population of cells performing functions previously attributed to MG. Although GFPhi cells dominated the macrophage response to cone death in the photoreceptor cell layer, their ablation led to only an incremental increase in cone survival. The ability to identify, ablate, and isolate these cells will facilitate analysis of this activated, antigen-presenting subset of MG.
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影响因子：
32.4
作者：
Jung, S;Unutmaz, D;Lang, RA
通讯作者：
Lang, RA
影响因子：
4.4
作者：
Fan, Jie;Rohrer, Baerbel;Crouch, Rosalie K.
通讯作者：
Crouch, Rosalie K.
影响因子：
4.6
作者：
Roche SL;Wyse-Jackson AC;Ruiz-Lopez AM;Byrne AM;Cotter TG
通讯作者：
Cotter TG
影响因子：
4.6
作者：
O'Koren EG;Mathew R;Saban DR
通讯作者：
Saban DR
DOI：
10.1073/pnas.0503460102
发表时间：
2005-08-30
影响因子：
11.1
作者：
Moiseyev, G;Chen, Y;Ma, JX
通讯作者：
Ma, JX