WNT signaling in activated microglia is proinflammatory

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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.