Microglia-specific ADAM17 deficiency improves functional recovery after spinal cord injury

Abstract

After spinal cord injury (SCI), an excessive inflammatory reaction is provoked in which phagocytes play an important role. 'A disintegrin and metalloproteinase 17' (ADAM17) is an interesting target to modulate inflammation and phagocytosis since it sheds inflammatory mediators and phagocytic receptors. Our hypothesis is that ADAM17 deficiency favors an anti-inflammatory environment by the reduced shedding of inflammatory mediators and by enhancing phagocytosis improving functional recovery after SCI. SCI was induced in hypomorphic ADAM17 mice, mice treated with an ADAM17 inhibitor or microglia-specific ADAM17 knockout mice and functional recovery was evaluated and spinal cords were histologically analyzed. Furthermore, the in vitro phagocytic capacity of ADAM17 deficient macrophages and primary microglia was investigated. ADAM17 deficiency, ADAM17 inhibition or microglia-specific ADAM17 knockout improves functional recovery after SCI. Histological analysis revealed a decrease in MHC-II+ cells and an increased 5-HT+ fiber ratio. ADAM17 deficient macrophages showed in vitro an impaired phagocytosis of latex beads but an improved phagocytosis of apoptotic neurons. An improved phagocytosis of latex beads by ADAM17 deficient microglia was observed. In conclusion, this study provides evidence that ADAM17 and more specifically microglial ADAM17 is important in the functional recovery after SCI. Furthermore, we demonstrate that ADAM17 deficiency affects the in vitro phagocytic capacity of macrophages and primary microglia.