Neuroprotection of photoreceptors by combined inhibition of both Fas and autophagy pathways in P23H mice.

IF 8.1 1区 生物学 Q1 CELL BIOLOGY
Mengling Yang, Jingyu Yao, Lin Jia, Andrew J Kocab, David N Zacks
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引用次数: 0

Abstract

The P23H variant of rhodopsin (RHO) is a common cause of autosomal dominant retinitis pigmentosa (adRP). Our previous data have shown that both the Fas (CD95) death receptor and hyperactivation of autophagy contribute to photoreceptor (PR) death in a mouse model of P23H-RHO adRP. Individually, inhibition of Fas or suppression of autophagy flux improves PR survival and function. The purpose of this study is to examine whether combined inhibition of Fas receptor activation and reducing autophagy flux would have an additive effect on PR survival and function in the P23H mouse. We crossed the Lpr mouse (which contains a functional knockout of the Fas receptor) with the P23H mouse to generate the Lpr/P23H mouse. Hydroxychloroquine (HCQ) was given in the drinking water at P21 to reduce autophagy flux. As an alternative to genetic inhibition of the Fas receptor, pharmacological blockade of the Fas receptor was achieved using intravitreal injections of the Fas inhibitor, ONL1204, administered via intravitreal injection at P14 and 2 months of age. Fellow eyes were injected with vehicle solution as controls. PR cell death, structure and function of the retina, as well as the activation of immune cells, were evaluated. Consistent with previous data, the Lpr/P23H mice exhibited a decreased rate of photoreceptor degeneration and reduced inflammation compared with P23H. Treatment of these mice with HCQ further preserved photoreceptor survival and function lowered the activation of immune cells, and resulted in reduced production of inflammatory cytokines in the retina. These results were recapitulated in HCQ-treated P23H mice receiving intravitreal injections of ONL1204. Our data suggest that in the mouse model of P23H adRD, inhibition of both the Fas pathway and autophagy pathways results in a greater protective effect, demonstrating the potential multipronged therapeutic approach to reduce PR death and improve retinal function in patients with P23H.

联合抑制Fas和自噬途径对P23H小鼠光受体的神经保护作用。
视紫红质(RHO)的P23H变异是常染色体显性视网膜色素变性(adRP)的常见原因。我们之前的数据表明,在P23H-RHO adRP小鼠模型中,Fas (CD95)死亡受体和自噬过度激活都有助于光受体(PR)死亡。单独地,抑制Fas或抑制自噬通量可改善PR的存活和功能。本研究的目的是研究联合抑制Fas受体激活和减少自噬通量是否会对P23H小鼠PR存活和功能产生累加效应。我们将Lpr小鼠(含有Fas受体的功能性敲除)与P23H小鼠杂交,生成Lpr/P23H小鼠。在P21时给予饮用水羟氯喹(HCQ)以降低自噬通量。作为基因抑制Fas受体的替代方法,在P14和2月龄时通过玻璃体腔注射Fas抑制剂ONL1204来实现Fas受体的药理学阻断。其他的眼睛注射了车辆溶液作为对照。观察PR细胞的死亡、视网膜的结构和功能以及免疫细胞的活化情况。与先前的数据一致,与P23H相比,Lpr/P23H小鼠表现出更低的光感受器变性率和更少的炎症。用HCQ治疗这些小鼠进一步保存了光感受器的存活和功能,降低了免疫细胞的激活,并导致视网膜中炎症细胞因子的产生减少。这些结果在hcq处理的P23H小鼠接受玻璃体内注射ONL1204后得到了重现。我们的数据表明,在P23H adRD小鼠模型中,抑制Fas途径和自噬途径均可产生更大的保护作用,表明P23H患者可能采用多管齐下的治疗方法来减少PR死亡和改善视网膜功能。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cell Death & Disease
Cell Death & Disease CELL BIOLOGY-
CiteScore
15.10
自引率
2.20%
发文量
935
审稿时长
2 months
期刊介绍: Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism. Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following: Experimental medicine Cancer Immunity Internal medicine Neuroscience Cancer metabolism
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