Erythropoietin and Wnt1 Govern Pathways of mTOR, Apaf-1, and XIAP in Inflammatory Microglia

Abstract

Inflammatory microglia modulate a host of cellular processes in the central nervous system that include neuronal survival, metabolic fluxes, foreign body exclusion, and cellular regeneration. Elucidation of the pathways that oversee microglial survival and integrity may offer new avenues for the treatment of neurodegenerative disorders. Here we demonstrate that erythropoietin (EPO), an emerging strategy for immune system modulation, prevents microglial early and late apoptotic injury during oxidant stress through Wnt1, a cysteine-rich glycosylated protein that modulates cellular development and survival. Loss of Wnt1 through blockade of Wnt1 signaling or through the gene silencing of Wnt1 eliminates the protective capacity of EPO. Furthermore, endogenous Wnt1 in microglia is vital to preserve microglial survival since loss of Wnt1 alone increases microglial injury during oxidative stress. Cellular protection by EPO and Wnt1 intersect at the level of protein kinase B (Akt1), the mammalian target of rapamycin (mTOR), and p70S6K, which are necessary to foster cytoprotection for microglia. Downstream from these pathways, EPO and Wnt1 control “anti-apoptotic” pathways of microglia through the modulation of mitochondrial membrane permeability, the release of cytochrome c, and the expression of apoptotic protease activating factor-1 (Apaf-1) and X-linked inhibitor of apoptosis protein (XIAP). These studies offer new insights for the development of innovative therapeutic strategies for neurodegenerative disorders that focus upon inflammatory microglia and novel signal transduction pathways.

WISP1: Clinical Insights for a Proliferative and Restorative Member of the CCN Family

“…Without mTOR activation, Wnt1 has been shown to lose the ability to support cellular proliferation [179]. The growth factor EPO requires Wnt1, mTOR, and p70S6K to foster cytoprotection for microglial cells during oxidant stress [25] and during Aβ toxicity [26]. …”

Programming Apoptosis and Autophagy with Novel Approaches for Diabetes Mellitus

“…For example, erythropoietin (EPO), a cytokine and an investigational therapeutic strategy for DM (12, 225), targets multiple cellular signal transduction pathways in the body (226, 227) and relies upon mTOR for cytoprotection (2, 32, 42, 199, 228). EPO uses mTOR to increase cell survival during oxygen-glucose deprivation (195, 229), prevent cell injury during β-amyloid exposure (230), modulate bone homeostasis (231), improve cognitive function sepsis-associated encephalopathy (232), promote retinal progenitor cell survival during oxidant stress (233), prevent retinal degeneration in models of polycystic kidney disease (62), and foster the neuronal phenotype of adult neuronal precursor cells (234). During abnormalities in cellular metabolism, EPO facilitates wound healing during DM (50), attenuates AGE-induced toxicity (235), protects endothelial cell survival during experimental models of DM (66, 67), maintains cellular mitochondrial function and energy metabolism (70), limits high glucose-induced oxidative stress in renal tubular cells (138), and reduces the detrimental effects of obesity in animal models (14).…”

Cutting through the Complexities of mTOR for the Treatment of Stroke

“…Over-expression of wild type p70S6K or a rapamycin resistant form of the p70S6K kinase enhances the cytoprotective effect of insulin (95). Other growth factors similar to insulin, such as erythropoietin (EPO) (98), also have been reported to be dependent upon mTOR activation for cytoprotection against apoptosis (86, 99, 100). …”