Using the cuprizone-induced toxicity model, the role of Bruton’s tyrosine kinase (BTK) signalling in modulating inflammation in microglial cells was assessed [1]. Results showed that BTK-dependent inflammatory signalling in these cells can be modulated using brain-penetrant BTK inhibitors in vivo. This treatment may suppress microglia-driven neuroinflammation in MS progression.
BTK is expressed in B-lymphocytes and monocytes/macrophages as well as in microglia. It is assumed to modulate the activity of both adaptive and innate immune cells. In B cells, BTK is centrally involved in the B-cell receptor signalling pathway, regulating proliferation, maturation, antigen presentation, and production of secreted immunoglobulins. The research that was reported focused on the possible role of BTK in regulating microglial deleterious inflammatory signalling.
This role was evaluated applying immunohistochemistry, Western blotting, and RNA sequencing in 3 different settings: primary murine microglial cells in vitro, a rodent model of cuprizone-induced demyelination, and post mortem MS brain tissue.
In mouse microglial cells, basal BTK activity was enhanced by stimulation with immune complexes and silenced with a BTK inhibitor. In autopsy tissue specimens, expression of BTK could be demonstrated in B cells and microglial cells; in MS lesion samples, levels were increased. Furthermore, a BTK-dependent transcriptional profile in brains from cuprizone-treated mice was identified. It was postulated that a brain-penetrant BTK inhibitor might provide therapeutic benefit within the CNS. Oral administration was found to downregulate the BTK-dependent gene expression signature in the mouse model.
- Gruber R, et al. Decoding Bruton’s tyrosine kinase signalling in neuroinflammation. MSVirtual 2020, Abstract P0311.
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