| dc.description.abstracteng | Controlling disease progression in multiple sclerosis (MS) remains a major challenge. Progression of MS is defined as an increase in neurological disability occurring independently of relapses or focal MRI-detectable inflammatory lesions. Whereas the exact mechanisms of progression are still unknown, it is assumed to be driven by an interplay of central nervous system (CNS)-resident cells and hematopoietic cells within the CNS.
The potential of B cells to modulate CNS-compartmentalized inflammation in progressive disease is of growing interest, since B cells are known to persist in the inflamed MS CNS and B cell-follicle like structures were found in the meninges of MS patients. Whether and how B cells interact with CNS-resident cells, such as microglia and astrocytes, to possibly modulate chronic progression of MS remains unclear.
In the first part of this study, the interaction of B cells with CNS-resident cells in modulation of chronic CNS inflammation was investigated. It was observed that B cells are capable of shaping the activity of microglia and astrocytes. B cells and their supernatant showed an upregulation of pro-inflammatory molecules on homeostatic microglia and astrocytes, while under inflammatory conditions the pro-inflammatory cytokine profile of microglia was reduced. It was identified that this effect is attributed to a soluble factor of B cells and showed that B cell-derived IL-10 has the potential of limiting microglia activity and function. In contrast, astrocyte activity was unaffected by B cell-derived IL-10. Taken together, these data demonstrate that the sole presence of B cells within the CNS is not by definition associated with pathogenic functions and reveal an immunoregulatory potential for controlling CNS-intrinsic inflammation, which is associated with disease progression.
The second part of this study aimed at analyzing the potential of Bruton’s tyrosine kinase (BTK) inhibition as a therapeutic strategy on CNS-resident cells in halting disease progression. BTK is an enzyme involved in B cell and myeloid cell activation and function. In the present study it was shown that the majority of CNS-resident cells expressing BTK are microglia cells and that its expression is increased upon activation. Evobrutinib inhibited microglial M1 polarization and enhanced the phagocytic capacity of microglia in vitro. Additionally, in the passive experimental autoimmune encephalomyelitis (EAE) animal model of MS, which vastly excludes an involvement of peripheral immune cells, evobrutinib reduced the expression of markers involved in activation and antigen presentation on microglia. Furthermore, in the cuprizone model, evobrutinib treatment increased the number of oligodendrocyte precursor cells and induced remyelination. In conclusion, these data suggest that BTK-dependent inflammatory signaling in microglia cells can be modulated by evobrutinib. These findings highlight the therapeutic potential of BTK inhibition in counteracting chronic progression of MS. | de |