title: ADAM17 is a survival factor for microglial cells in vitro and in vivo after spinal cord injury in mice.
abstract: A disintegrin and metalloprotease 17 (ADAM17) is a sheddase with important substrates including tumor necrosis factor-α (TNF-α) 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-α 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-α, it increases expression of the pro-apoptotic marker Bax and microglial apoptosis while impairing functional recovery after SCI. These data suggest that ADAM17 is a key survival factor for microglial cells after SCI.
authors: Department of Morphology & Biomedical Research Institute, Hasselt University, Hasselt, Belgium.
authors: P M
authors: PM
authors: Vidal
authors: Department of Morphology & Biomedical Research Institute, Hasselt University, Hasselt, Belgium.
authors: E
authors: E
authors: Lemmens
authors: 1] Department of Physiology & Biomedical Research Institute, Hasselt University, Hasselt, Belgium [2] Developmental Neurology Unit, GIGA-Neurosciences, University of Liège, Liège, Belgium [3] Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of Liège, Liège, Belgium.
authors: A
authors: A
authors: Avila
authors: Department of Morphology & Biomedical Research Institute, Hasselt University, Hasselt, Belgium.
authors: T
authors: T
authors: Vangansewinkel
authors: Institute of Biochemistry, Christian Albrechts University, Kiel, Germany.
authors: A
authors: A
authors: Chalaris
authors: Institute of Biochemistry, Christian Albrechts University, Kiel, Germany.
authors: S
authors: S
authors: Rose-John
authors: Department of Morphology & Biomedical Research Institute, Hasselt University, Hasselt, Belgium.
authors: S
authors: S
authors: Hendrix
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000072198:ADAM17 Protein; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D011804:Quinolines / Q000494:pharmacology; D013119:Spinal Cord Injuries / Q000378:metabolism* / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C476910:BMS561392; D011804:Quinolines; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse