Wnt1, FoxO3a, and NF-κB oversee microglial integrity and activation during oxidant stress

Abstract

Elucidating the underlying mechanisms that govern microglial activation and survival is essential for the development of new treatment strategies for neurodegenerative disorders, since microglia serve not only as guardian sentries of the nervous system, but also play a significant role in determining neuronal and vascular cell fate. Here we show that endogenous and exogenous Wnt1 in inflammatory microglial cells is necessary for the prevention of apoptotic early membrane phosphatidylserine exposure and later DNA degradation, since blockade of Wnt1 signaling abrogates cell survival during oxidative stress. Wnt1 prevents apoptotic demise through the post-translational phosphorylation and maintenance of FoxO3a in the cytoplasm to inhibit an apoptotic cascade that relies upon the loss of mitochondrial membrane permeability, cytochrome c release, Bad phosphorylation, and activation of caspase 3 and caspase 1 as demonstrated by complimentary gene knockdown studies of FoxO3a. Furthermore, subcellular trafficking and gene knockdown studies of NF-κB p65 illustrate that microglial cell survival determined by Wnt1 during oxidative stress requires NF-κB p65. Our work highlights Wnt1 and the control of novel downstream transcriptional pathways as critical components for the oversight of nervous system microglial cells.

Wnt1 Positively Regulates CD36 Expression via TCF4 and PPAR-γ in Macrophages

“…In addition, Wnt1 promotes mammary tumorigenesis by inducing matrix metalloproteinase (MMP)-2, MMP-3, and MMP-9 [14]. Furthermore, Wnt1 promotes cell survival through NF-κB activation [15]. Recently, it has been reported that during the differentiation of dendritic cells from monocytes, Wnt1 was decreased by miR-34a [16].…”

Targeting erythropoietin for chronic neurodegenerative diseases

“…Phosphorylation of BAD promotes its interaction with the cytosolic docking protein 14-3-3 resulting in the liberation of the anti-apoptotic protein Bcl-2/Bcl-x L [13,41,67]. The phosphorylation of FoxO3a also results in its recruitment by the 14-3-3 protein and its cytoplasmic retention, rendering it unable to regulate its target genes in the nucleus for the induction of apoptosis [25,34,[68][69][70][71][72][73][74]. Inhibition of GSK-3b activity by phosphorylation through Akt can result in its inactivation and block the induction of apoptosis [33,75,76].…”

Type I Diabetes and the Role of Inflammatory-Related Cellular Signaling

“…FOXO3a, a critical mediator between growth factor IRS-1/PI3K/AKT and IRS2/MEK/ERK signaling, induces the expression of ubiquitin, atrogin-1, and MuRF1 (Tisdale; Zheng, Ohkawa et al; Sandri, Sandri et al 2004). In addition to atrogenes, FOXO3a is responsible for apoptotic signaling leading to the loss of mitochondrial membrane permeability, degradation of nuclear DNA, cytochrome c release, Bad phosphorylation, downregulation of FLICE-inhibitory protein, and cleaved (active) caspase 1, 3, and 8 (Hou, Chong et al;Shang, Chong et al;Skurk, Maatz et al 2004). Therefore, FOXO3a may represent a promising target for the treatment of T1DM-mediated skeletal muscle atrophy.…”