Neuronal p58<sup>IPK</sup> Protects Retinal Ganglion Cells Independently of Macrophage/Microglia Activation in Ocular Hypertension

oleh: Todd McLaughlin, Jinli Wang, Liyun Jia, Fuguo Wu, Yaqin Wang, Joshua J. Wang, Xiuqian Mu, Sarah X. Zhang

Format: Article
Diterbitkan: MDPI AG 2023-06-01

Deskripsi

p58<sup>IPK</sup> 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 p58<sup>IPK</sup> 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 p58<sup>IPK</sup> in the retina. However, the mechanisms remain elusive. Herein, we investigated the cellular mechanisms underlying the neuroprotection action of p58<sup>IPK</sup> using conditional knockout (cKO) mouse lines where p58<sup>IPK</sup> is deleted in retinal neurons (Chx10-p58<sup>IPK</sup> cKO) or in myeloid cells (Lyz2-p58<sup>IPK</sup> cKO). In addition, we overexpressed p58<sup>IPK</sup> by adeno-associated virus (AAV) in the retina to examine the effect of p58<sup>IPK</sup> on RGC survival after ocular hypertension (OHT) in wild type (WT) mice. Our results show that overexpression of p58<sup>IPK</sup> by AAV significantly improved RGC survival after OHT in WT mice, suggesting a protective effect of p58<sup>IPK</sup> on reducing RGC injury. Conditional knockout of p58<sup>IPK</sup> 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-p58<sup>IPK</sup> cKO mice. Deletion of p58<sup>IPK</sup> in retinal neurons exacerbates RGC loss at 14 days after OHT. In contrast, deficiency of p58<sup>IPK</sup> in myeloid cells increased the microglia/macrophage activation but had no effect on RGC loss. We conclude that deletion of p58<sup>IPK</sup> in macrophages increases their activation, but does not influence RGC survival. These results suggest that the neuroprotective action of p58<sup>IPK</sup> is mediated by its expression in retinal neurons, but not in macrophages. Therefore, targeting p58<sup>IPK</sup> specifically in retinal neurons is a promising approach for the treatment of neurodegenerative retinal diseases including glaucoma.