Polarized microtubule remodeling transforms the morphology of reactive microglia and drives cytokine release
Abstract Microglial reactivity is a pathological hallmark in many neurodegenerative diseases. During stimulation, microglia undergo complex morphological changes, including loss of their characteristic ramified morphology, which is routinely used to detect and quantify inflammation in the brain. How...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-10-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-41891-6 |
| _version_ | 1827709726314463232 |
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| author | Max Adrian Martin Weber Ming-Chi Tsai Caspar Glock Olga I. Kahn Lilian Phu Tommy K. Cheung William J. Meilandt Christopher M. Rose Casper C. Hoogenraad |
| author_facet | Max Adrian Martin Weber Ming-Chi Tsai Caspar Glock Olga I. Kahn Lilian Phu Tommy K. Cheung William J. Meilandt Christopher M. Rose Casper C. Hoogenraad |
| author_sort | Max Adrian |
| collection | DOAJ |
| description | Abstract Microglial reactivity is a pathological hallmark in many neurodegenerative diseases. During stimulation, microglia undergo complex morphological changes, including loss of their characteristic ramified morphology, which is routinely used to detect and quantify inflammation in the brain. However, the underlying molecular mechanisms and the relation between microglial morphology and their pathophysiological function are unknown. Here, proteomic profiling of lipopolysaccharide (LPS)-reactive microglia identifies microtubule remodeling pathways as an early factor that drives the morphological change and subsequently controls cytokine responses. We find that LPS-reactive microglia reorganize their microtubules to form a stable and centrosomally-anchored array to facilitate efficient cytokine trafficking and release. We identify cyclin-dependent kinase 1 (Cdk-1) as a critical upstream regulator of microtubule remodeling and morphological change in-vitro and in-situ. Cdk-1 inhibition also rescues tau and amyloid fibril-induced morphology changes. These results demonstrate a critical role for microtubule dynamics and reorganization in microglial reactivity and modulating cytokine-mediated inflammatory responses. |
| first_indexed | 2024-03-10T17:27:00Z |
| format | Article |
| id | doaj.art-07f1bdd5b8fc4c30814079f35fbb9f55 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:27:00Z |
| publishDate | 2023-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-07f1bdd5b8fc4c30814079f35fbb9f552023-11-20T10:08:10ZengNature PortfolioNature Communications2041-17232023-10-0114112010.1038/s41467-023-41891-6Polarized microtubule remodeling transforms the morphology of reactive microglia and drives cytokine releaseMax Adrian0Martin Weber1Ming-Chi Tsai2Caspar Glock3Olga I. Kahn4Lilian Phu5Tommy K. Cheung6William J. Meilandt7Christopher M. Rose8Casper C. Hoogenraad9Department of Neuroscience, Genentech, Inc.Department of Neuroscience, Genentech, Inc.Department of Neuroscience, Genentech, Inc.Department of OMNI Bioinformatics, Genentech Inc.Department of Neuroscience, Genentech, Inc.Department of Microchemistry, Proteomics and LipidomicsDepartment of Microchemistry, Proteomics and LipidomicsDepartment of Neuroscience, Genentech, Inc.Department of Microchemistry, Proteomics and LipidomicsDepartment of Neuroscience, Genentech, Inc.Abstract Microglial reactivity is a pathological hallmark in many neurodegenerative diseases. During stimulation, microglia undergo complex morphological changes, including loss of their characteristic ramified morphology, which is routinely used to detect and quantify inflammation in the brain. However, the underlying molecular mechanisms and the relation between microglial morphology and their pathophysiological function are unknown. Here, proteomic profiling of lipopolysaccharide (LPS)-reactive microglia identifies microtubule remodeling pathways as an early factor that drives the morphological change and subsequently controls cytokine responses. We find that LPS-reactive microglia reorganize their microtubules to form a stable and centrosomally-anchored array to facilitate efficient cytokine trafficking and release. We identify cyclin-dependent kinase 1 (Cdk-1) as a critical upstream regulator of microtubule remodeling and morphological change in-vitro and in-situ. Cdk-1 inhibition also rescues tau and amyloid fibril-induced morphology changes. These results demonstrate a critical role for microtubule dynamics and reorganization in microglial reactivity and modulating cytokine-mediated inflammatory responses.https://doi.org/10.1038/s41467-023-41891-6 |
| spellingShingle | Max Adrian Martin Weber Ming-Chi Tsai Caspar Glock Olga I. Kahn Lilian Phu Tommy K. Cheung William J. Meilandt Christopher M. Rose Casper C. Hoogenraad Polarized microtubule remodeling transforms the morphology of reactive microglia and drives cytokine release Nature Communications |
| title | Polarized microtubule remodeling transforms the morphology of reactive microglia and drives cytokine release |
| title_full | Polarized microtubule remodeling transforms the morphology of reactive microglia and drives cytokine release |
| title_fullStr | Polarized microtubule remodeling transforms the morphology of reactive microglia and drives cytokine release |
| title_full_unstemmed | Polarized microtubule remodeling transforms the morphology of reactive microglia and drives cytokine release |
| title_short | Polarized microtubule remodeling transforms the morphology of reactive microglia and drives cytokine release |
| title_sort | polarized microtubule remodeling transforms the morphology of reactive microglia and drives cytokine release |
| url | https://doi.org/10.1038/s41467-023-41891-6 |
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