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.