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Martin E
,
Aigrot MS
,
Grenningloh R
,
Stankoff B
,
Lubetzki C
,
Boschert U
,
Zalc B
.
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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 in vitro. However, the role of BTK in the CNS is unknown.
METHODS: Our aim was to investigate the effect of BTK inhibition on myelin repair in ex vivo and in vivo experimental models of demyelination and remyelination. The remyelination effect of a BTK inhibitor (BTKi; BTKi-1) was then investigated in LPC-induced demyelinated cerebellar organotypic slice cultures and metronidazole-induced demyelinated Xenopus MBP-GFP-NTR transgenic tadpoles.
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: Our data demonstrate that BTK inhibition is a promising therapeutic strategy for myelin repair.
Fig. 1. Increased BTK signal upon demyelination. Cerebellar organotypic slices from P9 Plp-GFP mouse (green oligodendrocytes and myelin) were maintained in culture (A) or subjected to LPC treatment at 6 days in vitro (DIV) for 16–17 h (B) before being immunostained for BTK (red) or p-BTK at DIV9. LPC treatment induced a demyelination (loss of GFP signal B, C) and a concomitant 8.5-fold increase in BTK signal (B, D). Similarly, p-BTK was also increased after LPC demyelination (E). (*p < 0.01; ***p < 0.0001). Scale bar = 100 μm.
Fig. 2. Detection of BTK in microglia and astrocytes. Cerebellar organotypic slices from P9 mouse, were maintained in culture and submitted to LPC treatment at DIV6 for 16–17 h. At DIV9 (i.e., peak of demyelination) immuno staining was performed for BTK (Red) and Iba1 (microglia, green). A–F: Small magnification of control (A–C), and after LPC-induced demyelination (D–F). G,H,J, and K: Higher magnification illustrating co-localisation of BTK and p-BTK in microglia labeled with Iba1 (G) or CD11-F4/80-CD68 (J) and astrocyte S100ß+ (H, K).L: An example of two cells co-expressing BTK and p-BTK. Note that BTK is more at the surface while p-BTK is more intracytoplasmic. I and M: Quantification of microglia and astrocytes expressing BTK (I) or p-BTK (M). Scale bars: A–F = 20 μm; G,H, J,K, and L = 10 μm.
Fig. 4. Cellular expression of BTK in Xenopus and dose–response of remyelination by BTKi (BTKi-1). A–F: Immunodetection of BTK in microglial cells, but not in oligodendrocytes. Coronal (A–C) or horizontal (D–F) tissue sections across the brain stem of stage 52–53 MBP-GFP-NTR tadpoles double-labeled with anti-BTK (A, C, D, F, red) and anti-GFP (B, C, oligodendrocytes, green) antibodies or isolectin IB4 (E, F, microglia, white). Note in A–C the complete exclusion of the two labels, illustrating absence of BTK in oligodendrocytes. (D–F) In contrast, all BTK+ cells were also IB4+. However, some IB4+ cells (white arrows) were not BTK+. G: Demyelination of stage 52–53 MBP-GFP-NTR tadpoles was achieved by 10 days exposure to metronidazole (10 mM) in the swimming water. Tadpoles were then returned to normal water or water containing increasing concentration of BTKi (BTKi-1) for 3 days. Remyelination was assayed by counting the number of GFP+ cells per optic nerve on day 3 of the repair period. Treatment of tadpoles with BTKi (BTKi-1) at concentrations ranging between 50 nM and 1 μM improved remyelination up to 1.7-foldcompared to spontaneous recovery (control) set as 1. (*p < 0.01; **p < 0.001). Scale bar in A–F = 20 μm.
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