ADAM17-deficiency on microglia but not on macrophages promotes phagocytosis and functional recovery after spinal cord injury

Daniela Sommer, Inge Corstjens, Selien Sanchez, Dearbhaile Dooley, Stefanie Lemmens, Jana Van Broeckhoven, Jeroen Bogie, Tim Vanmierlo, Pia M. Vidal, Stefan Rose-John, Myriam Gou-Fabregas, Sven Hendrix*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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 languageEnglish
Pages (from-to)129-145
Number of pages17
JournalBrain Behavior and Immunity
Volume80
DOIs
Publication statusPublished - 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

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