Soluble P-selectin promotes retinal ganglion cell survival through activation of Nrf2 signaling after ischemia injury

Abstract

Retinal ischemic injuries play an important role in the pathogenesis of several eye disorders. Inflammation and oxidative stress are key players in ischemic injuries. Following retinal ischemia, vascular endothelial cells and leukocytes express several inflammatory adhesion receptors, such as selectins and cell adhesion molecules. P-selectin stimulates leukocyte recruitment to platelet aggregates and has an important role in vascular homeostasis and inflammatory leukocyte extravasation. Soluble P-selectin can be neuroprotective through competitive binding to the receptors of endogenous P-selectin molecules. Here, we demonstrate the neuroprotective effect of a recombinant P-selectin immunoglobin G (P-sel-IgG) chimeric fusion protein in a rat anterior ischemic optic neuropathy (rAION) model. rAION was induced by photodynamic therapy. P-sel-IgG treatment reduced optic nerve edema and stabilized the blood–optic nerve barrier (BONB) in the acute phase of rAION. Further, P-sel-IgG increased the retinal ganglion cell (RGC) survival rate, reduced RGC apoptosis, preserved visual function, maintained retinal nerve fiber layer thickness, and reduced macrophage infiltration in optic nerve tissue in the chronic phase (day 28). Increased NAD(P)H quinone dehydrogenase 1 (NQO1) and heme oxygenase 1(HO-1) expression levels, along with increased transcription factor Nrf2, suggesting an antioxidant role of P-sel-IgG via the Nrf2 signaling pathway. In conclusion, this study is the first to demonstrate that P-sel-IgG treatment promotes RGC survival by stabilizing the BONB and activating the Nrf2 signaling pathway in a rAION model.

Regenerative Effects of Heme Oxygenase Metabolites on Neuroinflammatory Diseases

“…In the retina, HO-2 has been detected in the inner segment of photoreceptors, in amacrine cells, some bipolar and ganglion cells, and in some astrocytes [29], implying that CO and BR are synthesized by HO-2 and can diffuse into neighboring cells in physiological conditions in the retina. In pathologic conditions, CO induces the nuclear translocation and accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2) [30] and HO-1 is upregulated via Nrf2 after retinal ischemic injury [31].…”

Effect of Autophagy Regulated by Sirt1/FoxO1 Pathway on the Release of Factors Promoting Thrombosis from Vascular Endothelial Cells

“…Therefore, vWF is a promising target for the prevention of arterial thrombosis and AS. P-selectin is a member of the selectin family, which transfers to the surface of the vascular endothelial, mediates leukocyte recruitment and participates in inflammation and coagulation [7]. P-selectin, highly expressed on the surface of vascular endothelial with acute or chronic inflammation, is an ideal target for the prevention of AS [8].…”

Potential Protective and Therapeutic Roles of the Nrf2 Pathway in Ocular Diseases: An Update

“…Increases expressions of Nrf2, HO-1, NQO1, and GCLM in the retina, reduces inflammatory mediator expression, and reduces leukocyte adherence to retinal vasculature [121] RTA 408 RPEs Activates Nrf2 and increases the expression of its downstream genes, such as HO-1, NQO1, SOD2, catalase, Grx1, and Trx1 [242] Soluble P-selectin RGCs Increases NQO1 and HO-1 expression levels, along with increased transcription factor Nrf2 [243] Eriodictyol…”