Extracellular traps formation following cervical spinal cord injury

Abstract

Spinal cord injuries involve a primary injury that can lead to permanent loss of function and a secondary injury associated with pathologic and inflammatory processes. Extracellular traps are extracellular structures expressed by immune cells that are primarily composed of chromatin, granular enzymes and histones. Extracellular traps are known to induce tissue damage when overexpressed and could be associated in the occurrence of secondary damage.In the present study, we used flow cytometry to demonstrate that at 1 day following a C2 spinal cord lateral hemisection in male Swiss mice, resident microglia form vital microglia extracellular traps, and infiltrating neutrophils form vital neutrophil extracellular traps. We also used immunolabelling to show that microglia near the lesion area are most likely to form these microglia extracellular traps. As expected, infiltrating neutrophils are located at the site of injury, though only some of them engage in post-injury extracellular trap formation. We also observed the formation of microglia and neutrophil extracellular traps in our sham animal models of durotomy, but formation was less frequent than following the C2 hemisection. Our results demonstrate for the first time that microglia form extracellular traps in the spinal cord following injury and durotomy. It remains however to determine the exact mechanisms and kinetics of neutrophil and microglia extracellular traps formation following spinal cord injury. This information would allow to better mitigate this inflammatory process that may contribute to secondary injury and to effectively target extracellular traps to improve functional outcomes following spinal cord injury.

Chondroitin Sulfate Proteoglycans Revisited: Its Mechanism of Generation and Action for Spinal Cord Injury

“…Recent studies have shown that neutrophils promoted the overexpression of CSPGs in SCI by degranulating and forming neutrophil extracellular traps (NETs) [ 5 ]. Moreover, macrophages/microglia also form macrophages extracellular traps (METs) or microglia extracellular traps (MiETs) [ 21 , 22 ]. Furthermore, the signals released by these cells, which regulate the expression of CSPGs, converge on RAs and promote their overexpression through various mechanisms [ 11 - 14 ] ( Fig.…”

“…In recent years, NETs have been reported to have a unique role in aggravating inflammation and promoting astrocyte activation in SCI [ 5 ]. Moreover, recent research showed that microglia could also form ETs [ 21 ] ( Fig. 2 ).…”

“…Moreover, the dopamine-triggered ETs are independent of ROS formation and are not associated with cell death. Using flow cytometry and immunohistochemistry, Michel-Flutot et al demonstrated that ETs were formed in microglia at the early stage of SCI and were concentrated around the lesion core [ 21 ]. However, the formation mechanism and role of MiETs have not been discovered yet, which could be important in SCI studies.…”

Interleukin-17: A Putative Novel Pharmacological Target for Pathological Pain

“…IL-17 may express on NETs and triggers NETs [ 59 , 60 ]. Studies have shown that infiltrating neutrophils formed NETs after spinal cord injury [ 61 ]. Due to the web-like structure of NETs, uric acid could be captured leading to local uric acid accumulation and promoting hyperalgesia during muscle trauma [ 62 ].…”

ß1-adrenergic blockers preserve neuromuscular function by inhibiting the production of extracellular traps during systemic inflammation in mice

“…Dysregulation of NET formation can lead to deleterious outcomes such as vascular occlusions ( 18 ) and tissue damage ( 19 , 20 ). Recently, this production of ETs by infiltrating neutrophils was shown to be involved in neuroinflammatory processes associated with CNS diseases and CNS traumatic injuries ( 21 – 23 ), especially in BBB disruption, spinal cord edema aggravation, and neuronal apoptosis ( 24 ). Interestingly microglia, which are the first level of defense against pathogens infection by making phagocytosis and antigen presentation in the CNS ( 25 ) have been shown to also produce extracellular traps (MiETs) in vitro ( 26 – 28 ) and in vivo ( 21 , 28 ).…”