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WNT signaling in activated microglia is proinflammatory.

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 mic... Full description

Journal Title: Glia January 2011, Vol.59(1), pp.119-131
Main Author: Halleskog, Carina
Other Authors: Mulder, Jan , Dahlström, Jenny , Mackie, Ken , Hortobágyi, Tibor , Tanila, Heikki , Kumar Puli, Lakshman , Färber, Katrin , Harkany, Tibor , Schulte, Gunnar
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1098-1136 ; DOI: 10.1002/glia.21081
Link: http://search.proquest.com/docview/787045278/?pq-origsite=primo
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title: WNT signaling in activated microglia is proinflammatory.
format: Article
creator:
  • Halleskog, Carina
  • Mulder, Jan
  • Dahlström, Jenny
  • Mackie, Ken
  • Hortobágyi, Tibor
  • Tanila, Heikki
  • Kumar Puli, Lakshman
  • Färber, Katrin
  • Harkany, Tibor
  • Schulte, Gunnar
subjects:
  • Alzheimer Disease–Metabolism
  • Analysis of Variance–Metabolism
  • Animals–Genetics
  • Blotting, Western–Metabolism
  • Brain–Genetics
  • Cells, Cultured–Metabolism
  • Cytokines–Genetics
  • Enzyme-Linked Immunosorbent Assay–Metabolism
  • Frizzled Receptors–Drug Effects
  • Gene Expression Profiling–Metabolism
  • Humans–Drug Effects
  • Immunohistochemistry–Genetics
  • Inflammation–Metabolism
  • Mice–Drug Effects
  • Microglia–Physiology
  • Phosphorylation–Genetics
  • RNA, Messenger–Metabolism
  • Reverse Transcriptase Polymerase Chain Reaction–Pharmacology
  • Signal Transduction–Genetics
  • Wnt Proteins–Metabolism
  • Beta Catenin–Metabolism
  • Cytokines
  • Frizzled Receptors
  • RNA, Messenger
  • Wnt Proteins
  • Beta Catenin
ispartof: Glia, January 2011, Vol.59(1), pp.119-131
description: 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 Delta *b-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 Delta *b-catenin signaling in microglia in vivo by showing age-dependent Delta *b-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 Delta *b-catenin. WNT-3A dose dependently induces LRP6 phosphorylation with downstream activation of disheveled, Delta *b-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 . In summary, our data suggest that the WNT family of lipoglycoproteins can instruct proinflammatory microglia transformation and emphasize the pathogenic significance of Delta *b-catenin-signaling networks in this cell type. ? 2010 Wiley-Liss, Inc.
language: eng
source:
identifier: E-ISSN: 1098-1136 ; DOI: 10.1002/glia.21081
fulltext: fulltext
issn:
  • 10981136
  • 1098-1136
url: Link


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titleWNT signaling in activated microglia is proinflammatory.
creatorHalleskog, Carina ; Mulder, Jan ; Dahlström, Jenny ; Mackie, Ken ; Hortobágyi, Tibor ; Tanila, Heikki ; Kumar Puli, Lakshman ; Färber, Katrin ; Harkany, Tibor ; Schulte, Gunnar
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ispartofGlia, January 2011, Vol.59(1), pp.119-131
identifierE-ISSN: 1098-1136 ; DOI: 10.1002/glia.21081
subjectAlzheimer Disease–Metabolism ; Analysis of Variance–Metabolism ; Animals–Genetics ; Blotting, Western–Metabolism ; Brain–Genetics ; Cells, Cultured–Metabolism ; Cytokines–Genetics ; Enzyme-Linked Immunosorbent Assay–Metabolism ; Frizzled Receptors–Drug Effects ; Gene Expression Profiling–Metabolism ; Humans–Drug Effects ; Immunohistochemistry–Genetics ; Inflammation–Metabolism ; Mice–Drug Effects ; Microglia–Physiology ; Phosphorylation–Genetics ; RNA, Messenger–Metabolism ; Reverse Transcriptase Polymerase Chain Reaction–Pharmacology ; Signal Transduction–Genetics ; Wnt Proteins–Metabolism ; Beta Catenin–Metabolism ; Cytokines ; Frizzled Receptors ; RNA, Messenger ; Wnt Proteins ; Beta Catenin
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descriptionMicroglia 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 Delta *b-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 Delta *b-catenin signaling in microglia in vivo by showing age-dependent Delta *b-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 Delta *b-catenin. WNT-3A dose dependently induces LRP6 phosphorylation with downstream activation of disheveled, Delta *b-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 . In summary, our data suggest that the WNT family of lipoglycoproteins can instruct proinflammatory microglia transformation and emphasize the pathogenic significance of Delta *b-catenin-signaling networks in this cell type. ? 2010 Wiley-Liss, Inc.
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titleWNT signaling in activated microglia is proinflammatory.
authorHalleskog, Carina ; Mulder, Jan ; Dahlström, Jenny ; Mackie, Ken ; Hortobágyi, Tibor ; Tanila, Heikki ; Kumar Puli, Lakshman ; Färber, Katrin ; Harkany, Tibor ; Schulte, Gunnar
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