INPP5D regulates inflammasome activation in human microglia
Abstract Microglia and neuroinflammation play an important role in the development and progression of Alzheimer’s disease (AD). Inositol polyphosphate-5-phosphatase D (INPP5D/SHIP1) is a myeloid-expressed gene genetically-associated with AD. Through unbiased analyses of RNA and protein profiles in I...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-42819-w |
| _version_ | 1827603348686110720 |
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| author | Vicky Chou Richard V. Pearse Aimee J. Aylward Nancy Ashour Mariko Taga Gizem Terzioglu Masashi Fujita Seeley B. Fancher Alina Sigalov Courtney R. Benoit Hyo Lee Matti Lam Nicholas T. Seyfried David A. Bennett Philip L. De Jager Vilas Menon Tracy L. Young-Pearse |
| author_facet | Vicky Chou Richard V. Pearse Aimee J. Aylward Nancy Ashour Mariko Taga Gizem Terzioglu Masashi Fujita Seeley B. Fancher Alina Sigalov Courtney R. Benoit Hyo Lee Matti Lam Nicholas T. Seyfried David A. Bennett Philip L. De Jager Vilas Menon Tracy L. Young-Pearse |
| author_sort | Vicky Chou |
| collection | DOAJ |
| description | Abstract Microglia and neuroinflammation play an important role in the development and progression of Alzheimer’s disease (AD). Inositol polyphosphate-5-phosphatase D (INPP5D/SHIP1) is a myeloid-expressed gene genetically-associated with AD. Through unbiased analyses of RNA and protein profiles in INPP5D-disrupted iPSC-derived human microglia, we find that reduction in INPP5D activity is associated with molecular profiles consistent with disrupted autophagy and inflammasome activation. These findings are validated through targeted pharmacological experiments which demonstrate that reduced INPP5D activity induces the formation of the NLRP3 inflammasome, cleavage of CASP1, and secretion of IL-1β and IL-18. Further, in-depth analyses of human brain tissue across hundreds of individuals using a multi-analytic approach provides evidence that a reduction in function of INPP5D in microglia results in inflammasome activation in AD. These findings provide insights into the molecular mechanisms underlying microglia-mediated processes in AD and highlight the inflammasome as a potential therapeutic target for modulating INPP5D-mediated vulnerability to AD. |
| first_indexed | 2024-03-09T05:37:53Z |
| format | Article |
| id | doaj.art-9e3d8cd8d32347f6b00af0ac1594f3b7 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-09T05:37:53Z |
| publishDate | 2023-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-9e3d8cd8d32347f6b00af0ac1594f3b72023-12-03T12:27:28ZengNature PortfolioNature Communications2041-17232023-11-0114112310.1038/s41467-023-42819-wINPP5D regulates inflammasome activation in human microgliaVicky Chou0Richard V. Pearse1Aimee J. Aylward2Nancy Ashour3Mariko Taga4Gizem Terzioglu5Masashi Fujita6Seeley B. Fancher7Alina Sigalov8Courtney R. Benoit9Hyo Lee10Matti Lam11Nicholas T. Seyfried12David A. Bennett13Philip L. De Jager14Vilas Menon15Tracy L. Young-Pearse16Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical SchoolAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical SchoolAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical SchoolAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical SchoolCenter for Translational and Computational Neuroimmunology, Department of Neurology, and the Taub Institute for the Study of Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical CenterAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical SchoolCenter for Translational and Computational Neuroimmunology, Department of Neurology, and the Taub Institute for the Study of Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical CenterAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical SchoolCenter for Translational and Computational Neuroimmunology, Department of Neurology, and the Taub Institute for the Study of Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical CenterAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical SchoolAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical SchoolCenter for Translational and Computational Neuroimmunology, Department of Neurology, and the Taub Institute for the Study of Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical CenterDepartment of Biochemistry, Emory School of MedicineRush Alzheimer’s Disease Center, Rush University Medical CenterCenter for Translational and Computational Neuroimmunology, Department of Neurology, and the Taub Institute for the Study of Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical CenterCenter for Translational and Computational Neuroimmunology, Department of Neurology, and the Taub Institute for the Study of Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical CenterAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical SchoolAbstract Microglia and neuroinflammation play an important role in the development and progression of Alzheimer’s disease (AD). Inositol polyphosphate-5-phosphatase D (INPP5D/SHIP1) is a myeloid-expressed gene genetically-associated with AD. Through unbiased analyses of RNA and protein profiles in INPP5D-disrupted iPSC-derived human microglia, we find that reduction in INPP5D activity is associated with molecular profiles consistent with disrupted autophagy and inflammasome activation. These findings are validated through targeted pharmacological experiments which demonstrate that reduced INPP5D activity induces the formation of the NLRP3 inflammasome, cleavage of CASP1, and secretion of IL-1β and IL-18. Further, in-depth analyses of human brain tissue across hundreds of individuals using a multi-analytic approach provides evidence that a reduction in function of INPP5D in microglia results in inflammasome activation in AD. These findings provide insights into the molecular mechanisms underlying microglia-mediated processes in AD and highlight the inflammasome as a potential therapeutic target for modulating INPP5D-mediated vulnerability to AD.https://doi.org/10.1038/s41467-023-42819-w |
| spellingShingle | Vicky Chou Richard V. Pearse Aimee J. Aylward Nancy Ashour Mariko Taga Gizem Terzioglu Masashi Fujita Seeley B. Fancher Alina Sigalov Courtney R. Benoit Hyo Lee Matti Lam Nicholas T. Seyfried David A. Bennett Philip L. De Jager Vilas Menon Tracy L. Young-Pearse INPP5D regulates inflammasome activation in human microglia Nature Communications |
| title | INPP5D regulates inflammasome activation in human microglia |
| title_full | INPP5D regulates inflammasome activation in human microglia |
| title_fullStr | INPP5D regulates inflammasome activation in human microglia |
| title_full_unstemmed | INPP5D regulates inflammasome activation in human microglia |
| title_short | INPP5D regulates inflammasome activation in human microglia |
| title_sort | inpp5d regulates inflammasome activation in human microglia |
| url | https://doi.org/10.1038/s41467-023-42819-w |
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