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Glia. 2011 Jan;59(1):119-31. doi: 10.1002/glia.21081. Epub 2010 Oct 21.

WNT signaling in activated microglia is proinflammatory.

Author information

1
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.

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 β-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 β-catenin signaling in microglia in vivo by showing age-dependent β-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 β-catenin. WNT-3A dose dependently induces LRP6 phosphorylation with downstream activation of disheveled, β-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 α. In summary, our data suggest that the WNT family of lipoglycoproteins can instruct proinflammatory microglia transformation and emphasize the pathogenic significance of β-catenin-signaling networks in this cell type.

PMID:
20967887
PMCID:
PMC3064522
DOI:
10.1002/glia.21081
[Indexed for MEDLINE]
Free PMC Article

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