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| Item Type: | Article |
|---|---|
| Title: | Bruton's tyrosine kinase-bearing B cells and microglia in neuromyelitis optica spectrum disorder |
| Creators Name: | Liu, Y. and Huang, Z. and Zhang, T.X. and Han, B. and Yang, G. and Jia, D. and Yang, L. and Liu, Q. and Lau, A.Y.L. and Paul, F. and Verkhratsky, A. and Shi, F.D. and Zhang, C. |
| Abstract: | BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory autoimmune disease of the central nervous system that involves B-cell receptor signaling as well as astrocyte-microglia interaction, which both contribute to evolution of NMOSD lesions. MAIN BODY: Through transcriptomic and flow cytometry analyses, we found that Bruton's tyrosine kinase (BTK), a crucial protein of B-cell receptor was upregulated both in the blood and cerebrospinal fluid of NMOSD patients. Blockade of BTK with zanubrutinib, a highly specific BTK inhibitor, mitigated the activation and maturation of B cells and reduced production of causal aquaporin-4 (AQP4) autoantibodies. In a mouse model of NMO, we found that both BTK and pBTK expression were significantly increased in microglia. Transmission electron microscope scan demonstrated that BTK inhibitor ameliorated demyelination, edema, and axonal injury in NMO mice. In the same mice colocalization of GFAP and Iba-1 immunofluorescence indicated a noticeable increase of astrocytes-microglia interaction, which was alleviated by zanubrutinib. The smart-seq analysis demonstrated that treatment with BTK inhibitor instigated microglial transcriptome changes including downregulation of chemokine-related genes and genes involved in the top 5 biological processes related to cell adhesion and migration, which are likely responsible for the reduced crosstalk of microglia and astrocytes. CONCLUSIONS: Our results show that BTK activity is enhanced both in B cells and microglia and BTK inhibition contributes to the amelioration of NMOSD pathology. These data collectively reveal the mechanism of action of BTK inhibition and corroborate BTK as a viable therapeutic target. |
| Keywords: | Neuromyelitis Optica Spectrum Disorder, B Cells, Microglia, Bruton’s Tyrosine Kinase, Zanubrutinib, Animals, Mice |
| Source: | Journal of Neuroinflammation |
| ISSN: | 1742-2094 |
| Publisher: | BioMed Central |
| Volume: | 20 |
| Number: | 1 |
| Page Range: | 309 |
| Date: | 21 December 2023 |
| Official Publication: | https://doi.org/10.1186/s12974-023-02997-2 |
| PubMed: | View item in PubMed |
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