Wnt1, FoxO3a, and NF-kappaB oversee microglial integrity and activation during oxidant stress.
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-kappaB p65 illustrate that microglial cell survival determined by Wnt1 during oxidative stress requires NF-kappaB p65. Our work highlights Wnt1 and the control of novel downstream transcriptional pathways as critical components for the oversight of nervous system microglial cells.
Shang
Yan Chen
YC
Division of Cellular and Molecular Cerebral Ischemia, Department of Neurology, Wayne State University School of Medicine, 4201 St. Antoine, Detroit, MI 48201, USA.
Chong
Zhao Zhong
ZZ
Hou
Jinling
J
Maiese
Kenneth
K
D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D015687:Cell Hypoxia; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D045304:Cytochromes c / Q000378:metabolism; D019610:Cytoprotection; D053938:DNA Fragmentation; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D053078:Membrane Potential, Mitochondrial; D017628:Microglia / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress; D010718:Phosphatidylserines / Q000032:analysis; D021381:Protein Transport; D051155:Wnt1 Protein / Q000378:metabolism* / Q000502:physiology; D051025:bcl-Associated Death Protein / Q000378:metabolism
D051858:Forkhead Transcription Factors; D016328:NF-kappa B; D010718:Phosphatidylserines; D051155:Wnt1 Protein; D051025:bcl-Associated Death Protein; D045304:Cytochromes c; D020169:Caspases
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