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ADAM17 is a survival factor for microglial cells in vitro and in vivo after spinal cord injury in mice
P M Vidal1, E Lemmens1, A Avila2
1Department of Morphology & Biomedical Research Institute, Hasselt University, Hasselt, Belgium.
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.
Insights
Inhibiting ADAM17 after spinal cord injury (SCI) was intended to reduce inflammation. However, this study found ADAM17 is crucial for microglial survival, and its inhibition worsens outcomes in SCI.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- ADAM17 (A disintegrin and metalloprotease 17) is a sheddase enzyme involved in processing key proteins like TNF-α.
- Dysregulation of ADAM17 activity is implicated in inflammatory conditions, including spinal cord injury (SCI).
Purpose of the Study:
- To investigate the therapeutic potential of inhibiting ADAM17 to mitigate inflammation post-SCI.
- To elucidate the role of ADAM17 in cellular survival and functional recovery following SCI.
Main Methods:
- Utilized the specific ADAM17 inhibitor BMS-561392 in neuronal and glial cell cultures.
- Performed genetic ablation of ADAM17 in experimental models.
- Assessed cellular survival, apoptosis markers (Bax), protein shedding, and functional recovery in vivo after SCI.
Main Results:
- ADAM17 inhibition impaired oligodendrocyte and microglia survival, mediated by p44 MAPK signaling.
- Genetic deletion of ADAM17 led to increased microglial death.
- In vivo ADAM17 blockade increased microglial apoptosis and worsened functional recovery post-SCI, despite minimal changes in TNF-α shedding.
Conclusions:
- ADAM17 is essential for microglial survival following spinal cord injury.
- Targeting ADAM17 for anti-inflammatory purposes in SCI may have detrimental effects on crucial cell populations and functional recovery.
