Bruton's Tyrosine Kinase Inhibition Promotes Myelin Repair.
Myelin
Xenopus
cerebellar slice culture
demyelination
microglia
remyelination
Journal
Brain plasticity (Amsterdam, Netherlands)
ISSN: 2213-6312
Titre abrégé: Brain Plast
Pays: Netherlands
ID NLM: 101669568
Informations de publication
Date de publication:
01 Oct 2020
01 Oct 2020
Historique:
entrez:
7
12
2020
pubmed:
8
12
2020
medline:
8
12
2020
Statut:
epublish
Résumé
Microglia are the resident macrophages of the central nervous system (CNS). In multiple sclerosis (MS) and related experimental models, microglia have either a pro-inflammatory or a pro-regenerative/pro-remyelinating function. Inhibition of Bruton's tyrosine kinase (BTK), a member of the Tec family of kinases, has been shown to block differentiation of pro-inflammatory macrophages in response to granulocyte-macrophage colony-stimulating factor Our aim was to investigate the effect of BTK inhibition on myelin repair in Cellular detection of BTK and its activated form BTK-phospho-Y223 (p-BTK) was determined by immunohistochemistry in organotypic cerebellar slice cultures, before and after lysophosphatidylcholine (LPC)-induced demyelination. A low BTK signal detected by immunolabeling under normal conditions in cerebellar slices was in sharp contrast to an 8.5-fold increase in the number of BTK-positive cells observed in LPC-demyelinated slice cultures. Under both conditions, approximately 75% of cells expressing BTK and p-BTK were microglia and 25% were astrocytes. Compared with spontaneous recovery, treatment of demyelinated slice cultures and MTZ-demyelinated transgenic tadpoles with BTKi resulted in at least a 1.7-fold improvement of remyelination. Our data demonstrate that BTK inhibition is a promising therapeutic strategy for myelin repair.
Sections du résumé
BACKGROUND
BACKGROUND
Microglia are the resident macrophages of the central nervous system (CNS). In multiple sclerosis (MS) and related experimental models, microglia have either a pro-inflammatory or a pro-regenerative/pro-remyelinating function. Inhibition of Bruton's tyrosine kinase (BTK), a member of the Tec family of kinases, has been shown to block differentiation of pro-inflammatory macrophages in response to granulocyte-macrophage colony-stimulating factor
METHODS
METHODS
Our aim was to investigate the effect of BTK inhibition on myelin repair in
RESULTS
RESULTS
Cellular detection of BTK and its activated form BTK-phospho-Y223 (p-BTK) was determined by immunohistochemistry in organotypic cerebellar slice cultures, before and after lysophosphatidylcholine (LPC)-induced demyelination. A low BTK signal detected by immunolabeling under normal conditions in cerebellar slices was in sharp contrast to an 8.5-fold increase in the number of BTK-positive cells observed in LPC-demyelinated slice cultures. Under both conditions, approximately 75% of cells expressing BTK and p-BTK were microglia and 25% were astrocytes. Compared with spontaneous recovery, treatment of demyelinated slice cultures and MTZ-demyelinated transgenic tadpoles with BTKi resulted in at least a 1.7-fold improvement of remyelination.
CONCLUSION
CONCLUSIONS
Our data demonstrate that BTK inhibition is a promising therapeutic strategy for myelin repair.
Identifiants
pubmed: 33282676
doi: 10.3233/BPL-200100
pii: BPL200100
pmc: PMC7685672
doi:
Types de publication
Journal Article
Langues
eng
Pagination
123-133Informations de copyright
© 2020 – IOS Press and the authors. All rights reserved.
Déclaration de conflit d'intérêts
R. Grenningloh is an employee of EMD Serono, Billerica, MA, USA (a business of Merck KGaA, Darmstadt, Germany). U. Boschert is an employee of Merck Serono S.A., Eysin, Switzerland.
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