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BTK regulates microglial function and neuroinflammation in human stem cell models and mouse models of multiple sclerosis

Author

Listed:
  • Ross C. Gruber

    (Sanofi
    Takeda)

  • Gregory S. Wirak

    (Sanofi)

  • Anna S. Blazier

    (Sanofi)

  • Lan Lee

    (Sanofi)

  • Michael R. Dufault

    (Sanofi)

  • Nellwyn Hagan

    (Sanofi)

  • Nathalie Chretien

    (Sanofi
    Flagship Labs)

  • Michael LaMorte

    (Sanofi)

  • Timothy R. Hammond

    (Sanofi)

  • Agnes Cheong

    (Sanofi)

  • Sean K. Ryan

    (Sanofi)

  • Andrew Macklin

    (Sanofi)

  • Mindy Zhang

    (Sanofi)

  • Nilesh Pande

    (Sanofi
    Voyager Therapeutics Inc)

  • Evis Havari

    (Sanofi)

  • Timothy J. Turner

    (Sanofi)

  • Anthony Chomyk

    (Cleveland Clinic)

  • Emilie Christie

    (Cleveland Clinic)

  • Bruce D. Trapp

    (Cleveland Clinic)

  • Dimitry Ofengeim

    (Sanofi)

Abstract

Neuroinflammation in the central nervous system (CNS), driven largely by resident phagocytes, has been proposed as a significant contributor to disability accumulation in multiple sclerosis (MS) but has not been addressed therapeutically. Bruton’s tyrosine kinase (BTK) is expressed in both B-lymphocytes and innate immune cells, including microglia, where its role is poorly understood. BTK inhibition may provide therapeutic benefit within the CNS by targeting adaptive and innate immunity-mediated disease progression in MS. Using a CNS-penetrant BTK inhibitor (BTKi), we demonstrate robust in vivo effects in mouse models of MS. We further identify a BTK-dependent transcriptional signature in vitro, using the BTKi tolebrutinib, in mouse microglia, human induced pluripotent stem cell (hiPSC)-derived microglia, and a complex hiPSC-derived tri-culture system composed of neurons, astrocytes, and microglia, revealing modulation of neuroinflammatory pathways relevant to MS. Finally, we demonstrate that in MS tissue BTK is expressed in B-cells and microglia, with increased levels in lesions. Our data provide rationale for targeting BTK in the CNS to diminish neuroinflammation and disability accumulation.

Suggested Citation

  • Ross C. Gruber & Gregory S. Wirak & Anna S. Blazier & Lan Lee & Michael R. Dufault & Nellwyn Hagan & Nathalie Chretien & Michael LaMorte & Timothy R. Hammond & Agnes Cheong & Sean K. Ryan & Andrew Mac, 2024. "BTK regulates microglial function and neuroinflammation in human stem cell models and mouse models of multiple sclerosis," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54430-8
    DOI: 10.1038/s41467-024-54430-8
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    References listed on IDEAS

    as
    1. Martina Absinta & Dragan Maric & Marjan Gharagozloo & Thomas Garton & Matthew D. Smith & Jing Jin & Kathryn C. Fitzgerald & Anya Song & Poching Liu & Jing-Ping Lin & Tianxia Wu & Kory R. Johnson & Dor, 2021. "A lymphocyte–microglia–astrocyte axis in chronic active multiple sclerosis," Nature, Nature, vol. 597(7878), pages 709-714, September.
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