Augmentation of CD47/SIRPα signaling protects cones in genetic models of retinal degeneration.
Augmentation of CD47/SIRPα signaling protects cones in genetic models of retinal degeneration.
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DOI：
10.1172/jci.insight.150796
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发表时间：
2021-08-23
期刊：
影响因子：
8
通讯作者：
Cepko CL
中科院分区：
文献类型：
--
作者：
Wang SK;Xue Y;Cepko CL
遗传性视网膜疾病，如视网膜色素变性（RP），可以由数千种不同的突变引起，其中一小部分已经成功地用基因替代治疗。然而，这种方法尚未扩大规模，在许多情况下可能不可行，这突出表明需要采取干预措施，使更多患者受益。在这里，我们发现，小胶质细胞的吞噬作用上调视锥细胞变性RP，这表明表达的“不要吃我”的信号，如CD 47可能赋予保护锥。为了测试这一点，我们递送了在视锥细胞上表达CD 47的腺相关病毒（AAV）载体，其在3种RP小鼠模型中促进视锥细胞存活并保留视觉功能。用CD 47进行的锥体拯救需要已知的相互作用蛋白，信号调节蛋白α（SIRPα），但不需要替代的相互作用蛋白，血小板反应蛋白-1（TSP 1）。尽管小胶质细胞吞噬作用增加与视锥细胞死亡之间存在相关性，但小胶质细胞对CD 47的促存活活性无明显影响，表明CD 47与非小胶质细胞上的SIRPα相互作用以减轻变性。这些发现确立了增强CD 47/SIRPα信号传导作为RP和可能的其他形式的神经变性的潜在治疗策略。
Inherited retinal diseases, such as retinitis pigmentosa (RP), can be caused by thousands of different mutations, a small number of which have been successfully treated with gene replacement. However, this approach has yet to scale and may not be feasible in many cases, highlighting the need for interventions that could benefit more patients. Here, we found that microglial phagocytosis is upregulated during cone degeneration in RP, suggesting that expression of “don’t-eat-me” signals such as CD47 might confer protection to cones. To test this, we delivered an adeno-associated viral (AAV) vector expressing CD47 on cones, which promoted cone survival in 3 mouse models of RP and preserved visual function. Cone rescue with CD47 required a known interacting protein, signal regulatory protein α (SIRPα), but not an alternative interacting protein, thrombospondin-1 (TSP1). Despite the correlation between increased microglial phagocytosis and cone death, microglia were dispensable for the prosurvival activity of CD47, suggesting that CD47 interacts with SIRPα on nonmicroglial cells to alleviate degeneration. These findings establish augmentation of CD47/SIRPα signaling as a potential treatment strategy for RP and possibly other forms of neurodegeneration.
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影响因子：
1.8
作者：
Abdejalil, J;Hamid, M;Serge, P
通讯作者：
Serge, P
影响因子：
17.1
作者：
Chan YK;Wang SK;Chu CJ;Copland DA;Letizia AJ;Costa Verdera H;Chiang JJ;Sethi M;Wang MK;Neidermyer WJ Jr;Chan Y;Lim ET;Graveline AR;Sanchez M;Boyd RF;Vihtelic TS;Inciong RGCO;Slain JM;Alphonse PJ;Xue Y;Robinson-McCarthy LR;Tam JM;Jabbar MH;Sahu B;Adeniran JF;Muhuri M;Tai PWL;Xie J;Krause TB;Vernet A;Pezone M;Xiao R;Liu T;Wang W;Kaplan HJ;Gao G;Dick AD;Mingozzi F;McCall MA;Cepko CL;Church GM
通讯作者：
Church GM
DOI：
10.1073/pnas.1721434116
发表时间：
2019-01-15
影响因子：
11.1
作者：
Hutter, Gregor;Theruvath, Johanna;Cheshier, Samuel H.
通讯作者：
Cheshier, Samuel H.
影响因子：
5.3
作者：
Jung, S;Aliberti, J;Littman, DR
通讯作者：
Littman, DR
DOI：
10.1084/jem.20200839
发表时间：
2021-03-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Deuse T;Hu X;Agbor-Enoh S;Jang MK;Alawi M;Saygi C;Gravina A;Tediashvili G;Nguyen VQ;Liu Y;Valantine H;Lanier LL;Schrepfer S
通讯作者：
Schrepfer S