The Immunomodulatory Functions of BTK Inhibition in the Central Nervous System

Abstract

Bruton's tyrosine kinase (BTK) is a central signaling node in B cells. BTK inhibition has witnessed great success in the treatment of B-cell malignancies. Additionally, in the immune system, BTK is also a prominent component linking a wide variety of immune-related pathways. Therefore, more and more studies attempting to dissect the role of BTK in autoimmune and inflammation progression have emerged in recent years. In particular, BTK expression was also found to be elevated within the central nervous system (CNS) during neuroinflammation. BTK inhibitors are capable of crossing the blood-brain barrier rapidly to modulate B cell functions, attenuate microglial activities and affect NLRP3 inflammasome pathways within the CNS to improve the outcome of diseases. Thus, BTK inhibition appears to be a promising approach to modulate dysregulated inflammation in the CNS and alleviate destruction caused by excessive inflammatory responses. This review will summarize the immunomodulatory mechanisms in which BTK is involved in the development of neurological diseases and discuss the therapeutic potential of BTK inhibition for the treatment of neuroinflammatory pathology.

Keywords: BTK; BTK inhibition; BTK inhibitors; neuroinflammation.

Figure 1

The structure of BTK. BTK consists of five protein domains from N to C terminal: a pleckstrin homology (PH) domain, a TEC homology (TH) domain, SRC homology (SH) domains SH2 and SH3, and a catalytic kinase domain. PIP3 interacts with the PH domain to recruit BTK to cell membrane. Next, SYK phosphorylates Y551 in the kinase domain, leading to autophosphorylation in Y233 in the SH3 domain to improve the catalytic activity of BTK. C481 is the binding site of covalent BTK inhibitors.

Figure 2

The overview of immunomodulatory mechanisms of BTK inhibition within CNS. In B cells, BTK inhibition dampens the capacity of antigen presentation, antibody secretion and pro-inflammatory cytokines production through BCR, TLR pathway and regulation of mitochondrial respiration. The M1 polarization toward a more pro-inflammatory profile, migration and pro-inflammatory cytokines production of microglia can be diminished by BTK inhibition. The activation of NLRP3 inflammasome in neurons and infiltrating macrophages/neutrophils can be inhibited by BTK inhibition, leading to decreased IL-1β production and neuroprotection.