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INPP5D regulates inflammasome activation in human microglia

Author

Listed:
  • Vicky Chou

    (Brigham and Women’s Hospital and Harvard Medical School)

  • Richard V. Pearse

    (Brigham and Women’s Hospital and Harvard Medical School)

  • Aimee J. Aylward

    (Brigham and Women’s Hospital and Harvard Medical School)

  • Nancy Ashour

    (Brigham and Women’s Hospital and Harvard Medical School)

  • Mariko Taga

    (Columbia University Irving Medical Center)

  • Gizem Terzioglu

    (Brigham and Women’s Hospital and Harvard Medical School)

  • Masashi Fujita

    (Columbia University Irving Medical Center)

  • Seeley B. Fancher

    (Brigham and Women’s Hospital and Harvard Medical School)

  • Alina Sigalov

    (Columbia University Irving Medical Center)

  • Courtney R. Benoit

    (Brigham and Women’s Hospital and Harvard Medical School)

  • Hyo Lee

    (Brigham and Women’s Hospital and Harvard Medical School)

  • Matti Lam

    (Columbia University Irving Medical Center)

  • Nicholas T. Seyfried

    (Emory School of Medicine
    Emory School of Medicine)

  • David A. Bennett

    (Rush University Medical Center)

  • Philip L. Jager

    (Columbia University Irving Medical Center)

  • Vilas Menon

    (Columbia University Irving Medical Center)

  • Tracy L. Young-Pearse

    (Brigham and Women’s Hospital and Harvard Medical School
    Harvard University)

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.

Suggested Citation

  • 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 & Nicho, 2023. "INPP5D regulates inflammasome activation in human microglia," Nature Communications, Nature, vol. 14(1), pages 1-23, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42819-w
    DOI: 10.1038/s41467-023-42819-w
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    References listed on IDEAS

    as
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