Abstract
A disintegrin and metalloproteinase 17 (ADAM17) is the major sheddase involved in the cleavage of a plethora of cytokines, cytokine receptors and growth factors, thereby playing a substantial role in inflammatory and regenerative processes after central nervous system trauma. By making use of a hypomorphic ADAM17 knockin mouse model as well as pharmacological ADAM10/ADAM17 inhibitors, we showed that ADAM17-deficiency or inhibition significantly increases clearance of apoptotic cells, promotes axon growth and improves functional recovery after spinal cord injury (SCI) in mice. Microglia-specific ADAM17-knockout (ADAM17flox(+/+)-Cx3Cr1 Cre(+/-)) mice also showed improved functional recovery similar to hypomorphic ADAM17 mice. In contrast, endothelial-specific (ADAM17flox(+/+)-Cdh5Pacs Cre(+/-)) and macrophage-specific (ADAM17flox(+/+)-LysM Cre(+/-)) ADAM17-knockout mice or bone marrow chimera with transplanted ADAM17-deficient macrophages, displayed no functional improvement compared to wild type mice. These data indicate that ADAM17 expression on microglia cells (and not on macrophages or endothelial cells) plays a detrimental role in inflammation and functional recovery after SCI.
Original language | English |
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Pages (from-to) | 129-145 |
Number of pages | 17 |
Journal | Brain Behavior and Immunity |
Volume | 80 |
DOIs | |
Publication status | Published - Aug 2019 |
Keywords
- ADAM17
- Inflammation
- Macrophages
- Microglia
- Spinal cord injury
- MAST-CELLS PROTECT
- TNF-ALPHA
- ALTERNATIVE ACTIVATION
- INFLAMMATORY RESPONSE
- CNS REMYELINATION
- UP-REGULATION
- REGENERATION
- DISINTEGRIN
- EXPRESSION