WNT signaling in activated microglia is proinflammatory

Carina Halleskog, Jan Mulder, Jenny Dahlström, Ken Mackie, Tibor Hortobágyi, Heikki Tanila, Lakshman Kumar Puli, Katrin Färber, Tibor Harkany, Gunnar Schulte

Research output: Contribution to journalArticle

109 Citations (Scopus)

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 FZD4,5,7,8 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.

Original languageEnglish
Pages (from-to)119-131
Number of pages13
JournalGlia
Volume59
Issue number1
DOIs
Publication statusPublished - Jan 2011

Keywords

  • Aging
  • Alzheimer's disease
  • Frizzled
  • Neurodegeneration
  • Neuroinflammation

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

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    Halleskog, C., Mulder, J., Dahlström, J., Mackie, K., Hortobágyi, T., Tanila, H., Kumar Puli, L., Färber, K., Harkany, T., & Schulte, G. (2011). WNT signaling in activated microglia is proinflammatory. Glia, 59(1), 119-131. https://doi.org/10.1002/glia.21081