Neutrophil Extracellular Traps Exacerbate Secondary Injury via Promoting Neuroinflammation and Blood–Spinal Cord Barrier Disruption in Spinal Cord Injury

Abstract

As the first inflammatory cell recruited to the site of spinal cord injury (SCI), neutrophils were reported to be detrimental to SCI. However, the precise mechanisms as to how neutrophils exacerbate SCI remain largely obscure. In the present study, we demonstrated that infiltrated neutrophils produce neutrophil extracellular traps (NETs), which subsequently promote neuroinflammation and blood–spinal cord barrier disruption to aggravate spinal cord edema and neuronal apoptosis following SCI in rats. Both inhibition of NETs formation by peptidylarginine deiminase 4 (PAD4) inhibitor and disruption of NETs by DNase 1 alleviate secondary damage, thus restraining scar formation and promoting functional recovery after SCI. Furthermore, we found that NETs exacerbate SCI partly via elevating transient receptor potential vanilloid type 4 (TRPV4) level in the injured spinal cord. Therefore, our results indicate that NETs might be a promising therapeutic target for SCI.

Experimental treatments to attenuate blood spinal cord barrier rupture in rats with traumatic spinal cord injury: A meta-analysis and systematic review

“…We considered that the high heterogeneity is due to differences in the extent of injury, measurement methods, and baseline conditions in rats across studies. All treatments, except one ( Feng et al, 2021 ), had statistically significant positive effects, indicating that the included treatment regimens had a positive effect on mitigating BSCB destruction. The forest plot showed that Xin et al (2021) had the greatest reduction (90%) in EB leakage, treated with BMSC-Exos.…”

“…We considered that the high heterogeneity is due to differences in the of injury, measurement methods, and baseline conditions in rats across studies. All treatments, except one (Feng et al, 2021), had statistically significant positive effects, 2019) treated with Protocatechuic acid (78%). These studies all achieved >70% reduction in EB leakage.…”

The immune microenvironment and tissue engineering strategies for spinal cord regeneration

“…Previous research has shown that NETs induce inflammatory responses and damage the BSCB, resulting in axonal degeneration, which is not conducive to neuronal regeneration. The arginine deaminase-4 peptide blocks the formation of NETs by DNAse-1, which reduces cell death and scar formation, thereby promoting functional recovery ( Feng et al, 2021 ). In addition, NETs accelerate endothelial cell injury and destroy the BSCB by increasing the expression of TRPV4.…”

Unveiling Leukocyte Extracellular Traps in Inflammatory Responses of the Central Nervous System

“…The activation of neutrophil PRRs by locally-produced DAMPs (171) results in a dramatic upregulation of pro-inflammatory cytokines, proteases and tissue-degrading enzymes, overall contributing to a harmful tissue environment (172). More recently, one study highlighted the detrimental effect of NETs formation in a clip-compression SCI model (173). Infiltrating neutrophils at lesion sites in the spinal cord release NETs, as measured by dsDNA dye Sytox, CitH3, and MPO staining, exacerbating both secondary fibrotic scar formation and the disruption of blood-spinal cord barrier, promoted by an increased endothelial expression of the transient receptor potential vanilloid type 4 (TRPV4), a calcium-permeable nonselective cation channel.…”