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

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