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

doi:10.1016/j.bbi.2019.02.032

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.

Highlights

Spinal cord injury (SCI) is characterized by a primary insult triggering a cascade of partially detrimental inflammatory processes, which aggravate initial tissue damage and impair neuronal regeneration (Beattie et al, 2002; Dooley et al, 2016; Gyoneva and Ransohoff, 2015)
We demonstrate for the first time that the absence of A disintegrin and metalloproteinase 17 (ADAM17) on microglia, but not macrophages or endothelial cells, promotes phagocytosis and improves histological and functional recovery after SCI in mice
We have used 4 different genetically modified mouse lines as well as bone marrow chimera to demonstrate in vivo that microglial ADAM17 plays a detrimental role in the inflammatory and regenerative processes after SCI

Summary

Introduction

Spinal cord injury (SCI) is characterized by a primary insult triggering a cascade of partially detrimental inflammatory processes, which aggravate initial tissue damage and impair neuronal regeneration (Beattie et al, 2002; Dooley et al, 2016; Gyoneva and Ransohoff, 2015). The resident immune cells of the central nervous system (CNS), and infiltrating monocyte-derived macrophages are major players in this neuroinflammatory response (David et al, 2015). Microglia and macrophages modulate the inflammatory response by secreting pro- and anti-inflammatory cytokines and by clearing noxious factors such as apoptotic/necrotic cells (David et al, 2015; Fu et al, 2016; Graeber, 2010; Horn et al, 2008). Activated microglia/macrophages are considered to be less inflammatory due to reduced secretion of pro-inflammatory cytokines and reduced production of nitric oxide compared to classically activated cells (David et al, 2015)

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