期刊
CELL DEATH & DISEASE
卷 4, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cddis.2013.466
关键词
TACE; TNF-alpha; ERK; MAPK; apoptosis; macrophage/microglia
类别
资金
- Deutsche Forschungsgemeinschaft [SPP1394]
- Research Foundation Flanders - FWO [G.0834.11N, G.0389.12N, GOA1413N, 1.2.703.10N]
- University Limburg
- [SFB877]
A disintegrin and metalloprotease 17 (ADAM17) is a sheddase with important substrates including tumor necrosis factor-alpha (TNF-alpha) and its receptors, the p75 neurotrophin receptor (p75NTR), and members of the epidermal growth factor family. The rationale of this study was to inhibit ADAM17-induced shedding of soluble TNF-alpha in order to reduce detrimental inflammation after spinal cord injury (SCI). However, using the specific ADAM17 blocker BMS-561392 in neuronal and glial cell cultures, we show that proper functioning of ADAM17 is vital for oligodendrocyte and microglia survival in a p44 MAPK-dependent manner. In contrast, genetic ablation of ADAM17 specifically increases microglial death. Surprisingly, although blocking ADAM17 in vivo does not substantially change the ratio between membrane-bound and soluble TNF-alpha, it increases expression of the pro-apoptotic marker Bax and microglial apoptosis while impairing functional recovery after SCI. These data suggest that ADAM 17 is a key survival factor for microglial cells after SCI.
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