Complement component 3 from astrocytes mediates retinal ganglion cell loss during neuroinflammation.
Complement component 3 from astrocytes mediates retinal ganglion cell loss during neuroinflammation.
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DOI：
10.1007/s00401-021-02366-4
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发表时间：
2021-11
影响因子：
12.7
通讯作者：
Calabresi PA
中科院分区：
文献类型：
--
作者：
Gharagozloo M;Smith MD;Jin J;Garton T;Taylor M;Chao A;Meyers K;Kornberg MD;Zack DJ;Ohayon J;Calabresi BA;Reich DS;Eberhart CG;Pardo CA;Kemper C;Whartenby KA;Calabresi PA
多发性硬化症(MS)是一种中枢神经系统(CNS)炎症性脱髓鞘疾病，以不同程度的继发性神经变性为特征。与视神经炎相关的MS患者视网膜神经节细胞(RGC)丢失，但神经元损伤的机制尚不清楚。补体成分C3与视网膜和大脑突触病理有关，这些病理可能先于神经变性。在这里，我们检查了死后的MS视网膜，然后使用小鼠模型-实验性自身免疫性脑脊髓炎(EAE)，来研究C3在视神经炎相关的RGC丢失的发病机制中的作用。首先，我们发现与非多发性硬化症患者的视网膜相比，多发性硬化症患者死后视网膜中广泛的C3表达(C3+/GFAP+细胞)和显著的RGC丢失(RBPMS+细胞)。1例有远期视神经炎病史的进展型多发性硬化症患者表现为明显的反应性星形胶质细胞增生症，C3表达在患眼的视网膜内层比对侧眼更深。为了研究C3是否介导视网膜变性，我们利用全球C3−/−EAE小鼠，发现与C3+/+EAE小鼠相比，它们的视网膜中RGC丢失较少，且部分保留了神经突起。C3−/−小鼠的视神经轴突肿胀较少，反映轴突损伤减轻，但脱髓鞘或T细胞渗入中枢神经系统的变化不明显。利用C3-tdTomato报告鼠系，我们展示了C3在EAE小鼠视网膜和视神经的星形胶质细胞中表达的确凿证据。星形胶质细胞中C3的条件性缺失显示RGC保护作用复制了在全局基因敲除中看到的效果。这些数据表明星形胶质细胞C3的表达是EAE和MS视网膜神经元病理的关键介质，并与最近的研究一致，研究表明C3基因变异与人类疾病中视网膜神经退行性变的速度更快有关。
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) characterized by varying degrees of secondary neurodegeneration. Retinal ganglion cells (RGC) are lost in MS in association with optic neuritis but the mechanisms of neuronal injury remain unclear. Complement component C3 has been implicated in retinal and cerebral synaptic pathology that may precede neurodegeneration. Herein, we examined post-mortem MS retinas, and then used a mouse model, experimental autoimmune encephalomyelitis (EAE), to examine the role of C3 in the pathogenesis of RGC loss associated with optic neuritis. First, we show extensive C3 expression in astrocytes (C3+/GFAP+ cells) and significant RGC loss (RBPMS+ cells) in post-mortem retinas from people with MS compared to retinas from non-MS individuals. A patient with progressive MS with a remote history of optic neuritis showed marked reactive astrogliosis with C3 expression in the inner retina extending into deeper layers in the affected eye more than the unaffected eye. To study whether C3 mediates retinal degeneration, we utilized global C3−/− EAE mice and found that they had less RGC loss and partially preserved neurites in the retina compared with C3+/+ EAE mice. C3−/− EAE mice had fewer axonal swellings in the optic nerve, reflecting reduced axonal injury, but had no changes in demyelination or T cell infiltration into the CNS. Using a C3-tdTomato reporter mouse line, we show definitive evidence of C3 expression in astrocytes in the retina and optic nerves of EAE mice. Conditional deletion of C3 in astrocytes showed RGC protection replicating the effects seen in the global knockouts. These data implicate astrocyte C3 expression as a critical mediator of retinal neuronal pathology in EAE and MS, and are consistent with recent studies showing C3 gene variants are associated with faster rates of retinal neurodegeneration in human disease.
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影响因子：
7.1
作者：
Ingram G;Loveless S;Howell OW;Hakobyan S;Dancey B;Harris CL;Robertson NP;Neal JW;Morgan BP
通讯作者：
Morgan BP
影响因子：
32.4
作者：
Hess C;Kemper C
通讯作者：
Kemper C
影响因子：
14.5
作者：
Fitzgerald, Kathryn C.;Kim, Kicheol;Calabresi, Peter A.
通讯作者：
Calabresi, Peter A.
影响因子：
3.3
作者：
Nytrova, Petra;Potlukova, Eliska;Trendelenburg, Marten
通讯作者：
Trendelenburg, Marten
影响因子：
4.6
作者：
Katschke KJ Jr;Xi H;Cox C;Truong T;Malato Y;Lee WP;McKenzie B;Arceo R;Tao J;Rangell L;Reichelt M;Diehl L;Elstrott J;Weimer RM;van Lookeren Campagne M
通讯作者：
van Lookeren Campagne M