BRUTON'S TYROSINE KINASE INHIBITION ENHANCES REMYELINATION VIA MICROGLIAL EXTRACELLULAR VESICLES

Myelin repair mechanisms are altered in demyelinating diseases such as multiple sclerosis (MS). Demyelinated axons are exposed to stressors, leading to neurodegeneration, especially in progressive MS. Nowadays, remyelination is an unmet therapeutic need. Even so, preclinical data have shown that Bruton's tyrosine kinase inhibitors (BTKi) by acting on myeloid cells, can delay MS progression. To date, remyelination has been tested in vitro using prenatal mouse models. Here, we test the effects of ibrutinib, a specific BTKi, on remyelination by proposing a novel in vitro model using cells derived from postnatal mice. First, we verified that postnatal mouse cultures remyelinated after L-α-lysophosphatidylcholine (LPC)-mediated demyelination. We then evaluated whether ibrutinib enhanced remyelination in this mouse model of demyelination/remyelination. Because BTK is mainly expressed in microglia, among the CNS cells, we hypothesized a remyelinating effect of ibrutinib mediated by these cells. The effects of ibrutinib are known to require crosstalk between BTK-expressing cells and OPCs. We observed a reduction in the release of EVs from inflamed microglial cells upon ibrutinib stimulation. In addition, we observed that ibrutinib-mediated remyelination depends on the change in EV content induced by ibrutinib, which was enriched in miR-223. One of the targets of miR223 is the mRNA coding for Statmhin-1, a tubulin polymerization destabilizing protein typically expressed by oligodendrocytes and overexpressed in MS patients. Altogether these data define one of the mechanisms that enables remyelination upon ibrutinib treatment and point to EVs released by microglia as an actor of increased remyelination, supporting the use of BTKi in MS.