机构：[1]Department of Ophthalmology and Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203, USA[2]Beijing Tongren Hospital, Capital Medical University, Beijing 100005, China首都医科大学附属北京同仁医院首都医科大学附属同仁医院[3]Taihe Hospital, Hubei University of Medicine, Shiyan 442005, China[4]Department of Biochemistry, University at Buffalo, State University of New York, Buffalo, NY 14203, USA[5]Aier Eye Hospital, Wuhan University, Wuhan 430074, China.
p58IPK is a multifaceted endoplasmic reticulum (ER) chaperone and a regulator of eIF2α kinases involved in a wide range of cellular processes including protein synthesis, ER stress response, and macrophage-mediated inflammation. Systemic deletion of p58IPK leads to age-related loss of retinal ganglion cells (RGC) and exacerbates RGC damage induced by ischemia/reperfusion and increased intraocular pressure (IOP), suggesting a protective role of p58IPK in the retina. However, the mechanisms remain elusive. Herein, we investigated the cellular mechanisms underlying the neuroprotection action of p58IPK using conditional knockout (cKO) mouse lines where p58IPK is deleted in retinal neurons (Chx10-p58IPK cKO) or in myeloid cells (Lyz2-p58IPK cKO). In addition, we overexpressed p58IPK by adeno-associated virus (AAV) in the retina to examine the effect of p58IPK on RGC survival after ocular hypertension (OHT) in wild type (WT) mice. Our results show that overexpression of p58IPK by AAV significantly improved RGC survival after OHT in WT mice, suggesting a protective effect of p58IPK on reducing RGC injury. Conditional knockout of p58IPK in retinal neurons or in myeloid cells did not alter retinal structure or cellular composition. However, a significant reduction in the b wave of light-adapted electroretinogram (ERG) was observed in Chx10-p58IPK cKO mice. Deletion of p58IPK in retinal neurons exacerbates RGC loss at 14 days after OHT. In contrast, deficiency of p58IPK in myeloid cells increased the microglia/macrophage activation but had no effect on RGC loss. We conclude that deletion of p58IPK in macrophages increases their activation, but does not influence RGC survival. These results suggest that the neuroprotective action of p58IPK is mediated by its expression in retinal neurons, but not in macrophages. Therefore, targeting p58IPK specifically in retinal neurons is a promising approach for the treatment of neurodegenerative retinal diseases including glaucoma.
基金：
This work was supported, in part, by NGR grant G2019302 (to S.X.Z.) from the BrightFocus
Foundation, NIH grants R01EY019949 (to S.X.Z.), R01EY025061 (to S.X.Z.), EY030970 (to S.X.Z.),
R01EY020545 (to X.M.), and R01EY029705 (to X.M.) from the National Eye Institute (NEI), and an
Unrestricted Grant from Research to Prevent Blindness to the Department of Ophthalmology, the
State University of New York at Buffalo.
第一作者机构：[1]Department of Ophthalmology and Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203, USA
通讯作者：
通讯机构：[1]Department of Ophthalmology and Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203, USA[4]Department of Biochemistry, University at Buffalo, State University of New York, Buffalo, NY 14203, USA
推荐引用方式(GB/T 7714)：
McLaughlin Todd,Wang Jinli,Jia Liyun,et al.Neuronal p58IPK Protects Retinal Ganglion Cells Independently of Macrophage/Microglia Activation in Ocular Hypertension[J].CELLS.2023,12(12):doi:10.3390/cells12121558.
APA：
McLaughlin Todd,Wang Jinli,Jia Liyun,Wu Fuguo,Wang Yaqin...&Zhang Sarah X.(2023).Neuronal p58IPK Protects Retinal Ganglion Cells Independently of Macrophage/Microglia Activation in Ocular Hypertension.CELLS,12,(12)
MLA：
McLaughlin Todd,et al."Neuronal p58IPK Protects Retinal Ganglion Cells Independently of Macrophage/Microglia Activation in Ocular Hypertension".CELLS 12..12(2023)
