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WNT signaling in activated microglia is proinflammatory

Item Type:Article
Title:WNT signaling in activated microglia is proinflammatory
Creators Name:Halleskog, C. and Mulder, J. and Dahlstroem, J. and Mackie, K. and Hortobagyi, T. and Tanila, H. and Kumar Puli, L. and Faerber, K. and Harkany, T. and Schulte, G.
Abstract:Microglia activation is central to the neuroinflammation associated with neurological and neurodegenerative diseases, particularly because activated microglia are often a source of proinflammatory cytokines. Despite decade-long research, the molecular cascade of proinflammatory transformation of microglia in vivo remains largely elusive. Here, we report increased beta-catenin expression, a central intracellular component of WNT signaling, in microglia undergoing a proinflammatory morphogenic transformation under pathogenic conditions associated with neuroinflammation such as Alzheimer's disease. We substantiate disease-associated beta-catenin signaling in microglia in vivo by showing age-dependent beta-catenin accumulation in mice with Alzheimer's-like pathology (APdE9). In cultured mouse microglia expressing the WNT receptors Frizzled FZD(4,5,7,8) and LDL receptor-related protein 5/6 (LRP5/6), we find that WNT-3A can stabilize beta-catenin. WNT-3A dose dependently induces LRP6 phosphorylation with downstream activation of disheveled, beta-catenin stabilization, and nuclear import. Gene-expression profiling reveals that WNT-3A stimulation specifically increases the expression of proinflammatory immune response genes in microglia and exacerbates the release of de novo IL-6, IL-12, and tumor necrosis factor alpha. In summary, our data suggest that the WNT family of lipoglycoproteins can instruct proinflammatory microglia transformation and emphasize the pathogenic significance of beta-catenin-signaling networks in this cell type.
Keywords:Aging, Alzheimer's Disease, Frizzled, Neurodegeneration, Neuroinflammation, Animals, Mice
Page Range:119-131
Date:January 2011
Official Publication:https://doi.org/10.1002/glia.21081
PubMed:View item in PubMed

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