%0 Journal Article
%T Heterotrimeric G protein-dependent WNT-5A signaling to ERK1/2 mediates distinct aspects of microglia proinflammatory transformation
%A Carina Halleskog
%A Jacomijn P Dijksterhuis
%A Michaela BC Kilander
%A Javier Becerril-Ortega
%A Carlos J Villaescusa
%A Eva Lindgren
%A Ernest Arenas
%A Gunnar Schulte
%J Journal of Neuroinflammation
%D 2012
%I BioMed Central
%R 10.1186/1742-2094-9-111
%X Mouse brain sections were used for immunohistochemistry. Primary isolated microglia and astrocytes were employed to characterize the WNT-induced inflammatory transformation and underlying intracellular signaling pathways by immunoblotting, quantitative mRNA analysis, proliferation and invasion assays. Further, measurements of G protein activation by [¦Ã-35£¿S]GTP binding, examination of calcium fluxes and cyclic AMP production were used to define intracellular signaling pathways.Astrocytes in the adult mouse brain express high levels of WNT-5A, which could serve as a novel astroglia-microglia communication pathway. The WNT-5A-induced proinflammatory microglia response is characterized by increased expression of inducible nitric oxide synthase, cyclooxygenase-2, cytokines, chemokines, enhanced invasive capacity and proliferation. Mapping of intracellular transduction pathways reveals that WNT-5A activates heterotrimeric Gi/o proteins to reduce cyclic AMP levels and to activate a Gi/o protein/phospholipase C/calcium-dependent protein kinase/extracellular signal-regulated kinase 1/2 (ERK1/2) axis. We show further that WNT-5A-induced ERK1/2 signaling is responsible for distinct aspects of the proinflammatory transformation, such as matrix metalloprotease 9/13 expression, invasion and proliferation.Thus, WNT-5A-induced and G protein-dependent signaling to ERK1/2 is important for the regulation of proinflammatory responses in mouse primary microglia cells. We show for the first time that WNT-5A/G protein signaling mediates physiologically important processes in primary mammalian cells with natural receptor and G protein stochiometry. Consequently, WNT-5A emerges as an important means of astrocyte-microglia communication and we, therefore, suggest WNT-5A as a new player in neuroinflammatory conditions, such as neurodegenerative disease, hypoxia, stroke, injury and infection.
%K Frizzled
%K Heterotrimeric G proteins
%K MAPK
%K Non-canonical WNT signaling
%K Cyclic AMP
%K Microglia
%K Neuroinflammation
%U http://www.jneuroinflammation.com/content/9/1/111/abstract