Heterotrimeric G protein-dependent WNT-5A signaling to ERK1/2 mediates distinct aspects of microglia proinflammatory transformation
<p><b>Abstract</b></p> <p><b>Background</b></p> <p>WNT-5A signaling in the central nervous system is important for morphogenesis, neurogenesis and establishment of functional connectivity; the source of WNT-5A and its importance for cellular comm...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2012-05-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | http://www.jneuroinflammation.com/content/9/1/111 |
| _version_ | 1811329016216420352 |
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| author | Halleskog Carina Dijksterhuis Jacomijn Kilander Michaela Brita Becerril-Ortega Javier Villaescusa Juan Lindgren Eva Arenas Ernest Schulte Gunnar |
| author_facet | Halleskog Carina Dijksterhuis Jacomijn Kilander Michaela Brita Becerril-Ortega Javier Villaescusa Juan Lindgren Eva Arenas Ernest Schulte Gunnar |
| author_sort | Halleskog Carina |
| collection | DOAJ |
| description | <p><b>Abstract</b></p> <p><b>Background</b></p> <p>WNT-5A signaling in the central nervous system is important for morphogenesis, neurogenesis and establishment of functional connectivity; the source of WNT-5A and its importance for cellular communication in the adult brain, however, are mainly unknown. We have previously investigated the inflammatory effects of WNT/β-catenin signaling in microglia in Alzheimer's disease. WNT-5A, however, generally recruits β-catenin-independent signaling. Thus, we aim here to characterize the role of WNT-5A and downstream signaling pathways for the inflammatory transformation of the brain's macrophages, the microglia.</p> <p><b>Methods</b></p> <p>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 [γ-<sup>35</sup> S]GTP binding, examination of calcium fluxes and cyclic AMP production were used to define intracellular signaling pathways.</p> <p><b>Results</b></p> <p>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 G<sub>i/o</sub> proteins to reduce cyclic AMP levels and to activate a G<sub>i/o</sub> 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.</p> <p><b>Conclusions</b></p> <p>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.</p> |
| first_indexed | 2024-04-13T15:36:20Z |
| format | Article |
| id | doaj.art-289c46415fd84cdb99fd44be24699f1d |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-04-13T15:36:20Z |
| publishDate | 2012-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-289c46415fd84cdb99fd44be24699f1d2022-12-22T02:41:16ZengBMCJournal of Neuroinflammation1742-20942012-05-019111110.1186/1742-2094-9-111Heterotrimeric G protein-dependent WNT-5A signaling to ERK1/2 mediates distinct aspects of microglia proinflammatory transformationHalleskog CarinaDijksterhuis JacomijnKilander Michaela BritaBecerril-Ortega JavierVillaescusa JuanLindgren EvaArenas ErnestSchulte Gunnar<p><b>Abstract</b></p> <p><b>Background</b></p> <p>WNT-5A signaling in the central nervous system is important for morphogenesis, neurogenesis and establishment of functional connectivity; the source of WNT-5A and its importance for cellular communication in the adult brain, however, are mainly unknown. We have previously investigated the inflammatory effects of WNT/β-catenin signaling in microglia in Alzheimer's disease. WNT-5A, however, generally recruits β-catenin-independent signaling. Thus, we aim here to characterize the role of WNT-5A and downstream signaling pathways for the inflammatory transformation of the brain's macrophages, the microglia.</p> <p><b>Methods</b></p> <p>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 [γ-<sup>35</sup> S]GTP binding, examination of calcium fluxes and cyclic AMP production were used to define intracellular signaling pathways.</p> <p><b>Results</b></p> <p>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 G<sub>i/o</sub> proteins to reduce cyclic AMP levels and to activate a G<sub>i/o</sub> 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.</p> <p><b>Conclusions</b></p> <p>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.</p>http://www.jneuroinflammation.com/content/9/1/111FrizzledHeterotrimeric G proteinsMAPKNon-canonical WNT signalingCyclic AMPMicrogliaNeuroinflammation |
| spellingShingle | Halleskog Carina Dijksterhuis Jacomijn Kilander Michaela Brita Becerril-Ortega Javier Villaescusa Juan Lindgren Eva Arenas Ernest Schulte Gunnar Heterotrimeric G protein-dependent WNT-5A signaling to ERK1/2 mediates distinct aspects of microglia proinflammatory transformation Journal of Neuroinflammation Frizzled Heterotrimeric G proteins MAPK Non-canonical WNT signaling Cyclic AMP Microglia Neuroinflammation |
| title | Heterotrimeric G protein-dependent WNT-5A signaling to ERK1/2 mediates distinct aspects of microglia proinflammatory transformation |
| title_full | Heterotrimeric G protein-dependent WNT-5A signaling to ERK1/2 mediates distinct aspects of microglia proinflammatory transformation |
| title_fullStr | Heterotrimeric G protein-dependent WNT-5A signaling to ERK1/2 mediates distinct aspects of microglia proinflammatory transformation |
| title_full_unstemmed | Heterotrimeric G protein-dependent WNT-5A signaling to ERK1/2 mediates distinct aspects of microglia proinflammatory transformation |
| title_short | Heterotrimeric G protein-dependent WNT-5A signaling to ERK1/2 mediates distinct aspects of microglia proinflammatory transformation |
| title_sort | heterotrimeric g protein dependent wnt 5a signaling to erk1 2 mediates distinct aspects of microglia proinflammatory transformation |
| topic | Frizzled Heterotrimeric G proteins MAPK Non-canonical WNT signaling Cyclic AMP Microglia Neuroinflammation |
| url | http://www.jneuroinflammation.com/content/9/1/111 |
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