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

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 Macklin, Mindy Zhang, Nilesh Pande, Evis Havari, Timothy J. Turner, Anthony Chomyk, Emilie Christie, Bruce D. Trapp and Dimitry Ofengeim ()
Additional contact information
Ross C. Gruber: Sanofi
Gregory S. Wirak: Sanofi
Anna S. Blazier: Sanofi
Lan Lee: Sanofi
Michael R. Dufault: Sanofi
Nellwyn Hagan: Sanofi
Nathalie Chretien: Sanofi
Michael LaMorte: Sanofi
Timothy R. Hammond: Sanofi
Agnes Cheong: Sanofi
Sean K. Ryan: Sanofi
Andrew Macklin: Sanofi
Mindy Zhang: Sanofi
Nilesh Pande: Sanofi
Evis Havari: Sanofi
Timothy J. Turner: Sanofi
Anthony Chomyk: Cleveland Clinic
Emilie Christie: Cleveland Clinic
Bruce D. Trapp: Cleveland Clinic
Dimitry Ofengeim: Sanofi

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-54430-8 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54430-8

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-54430-8

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().