BTK inhibition limits microglia-perpetuated CNS inflammation and promotes myelin repair

Area of Science:

• Neuroimmunology
• Cellular and Molecular Neuroscience

Background:

• Multiple sclerosis (MS) is characterized by chronic progression leading to persistent disability.
• This progression is driven by cells within the central nervous system (CNS) and is independent of relapses or new inflammatory lesions.
• Bruton's tyrosine kinase (BTK) plays a key role in activating immune cells like microglia and macrophages involved in MS pathology.

Purpose of the Study:

• To investigate the therapeutic potential of Bruton's tyrosine kinase (BTK) inhibition in counteracting chronic progression in multiple sclerosis (MS).
• To evaluate the effects of evobrutinib, a BTK inhibitor, on microglial activation and remyelination in preclinical models of MS.

Main Methods:

• Utilized chronic experimental autoimmune encephalomyelitis (EAE) and adoptive transfer models to study MS progression.
• Administered evobrutinib to inhibit BTK activity in these models.
• Assessed microglial pro-inflammatory activation and myelin debris clearance.
• Evaluated remyelination in a toxic demyelination model.

Main Results:

• Evobrutinib treatment reduced pro-inflammatory activation of microglia in chronic EAE and T-cell transfer models.
• BTK inhibition by evobrutinib promoted microglial clearance of myelin debris.
• This clearance facilitated accelerated remyelination in a toxic demyelination model.

Conclusions:

• Bruton's tyrosine kinase (BTK) inhibition, exemplified by evobrutinib, demonstrates potential in mitigating chronic MS progression.
• Targeting BTK may counteract key pathological processes in MS, including microglial activation and impaired remyelination.
• These findings support BTK inhibition as a promising strategy for managing progressive forms of MS.