Neutrophil extracellular traps aggravate neuronal endoplasmic reticulum stress and apoptosis via TLR9 after traumatic brain injury

Abstract

Endoplasmic reticulum (ER) stress and ER stress-mediated apoptosis play an important role during secondary brain damage after traumatic brain injury (TBI). Increased neutrophil extracellular traps (NETs) formation has been demonstrated to be associated with neurological damage after TBI. However, the correlation between ER stress and NETs remains unclear, and the specific function of NETs in neurons has not been defined. In this study, we found that the levels of NETs circulating biomarkers were remarkably elevated in the plasma of TBI patients. We then inhibited NETs formation by peptidylarginine deiminase 4 (PAD4, a critical enzyme for NETs formation) deficiency and discovered that ER stress activation and ER stress-mediated neuronal apoptosis were reduced. The degradation of NETs via DNase I showed similar outcomes. Furthermore, overexpression of PAD4 aggravated neuronal ER stress and ER stress-associated apoptosis, while TLR9 antagonist administration abrogated the damage caused by NETs. In addition to in vivo experiments, in vitro experiments revealed that treatment with a TLR9 antagonist alleviated NETs-induced ER stress and apoptosis in HT22 cells. Collectively, our results indicated that ER stress as well as the accompanying neuronal apoptosis can be ameliorated by disruption of NETs and that suppression of the TLR9-ER stress signaling pathway may contribute to positive outcomes after TBI.

An analysis of neutrophil-to-lymphocyte ratios and monocyte-to-lymphocyte ratios with six-month prognosis after cerebral contusions

“…Second, this difference can be attributed to the distinct functional characteristics of the two innate immune cells. Following a brain contusion, neutrophils rapidly accumulate at the damaged site and isolate or eliminate broken cell fragments via phagocytosis or a trap net created by cellular self-destruction ( 42 , 43 ). Neutrophils are unable to repeat these activities and have a short half-life; therefore, their involvement in the inflammatory response is dependent upon the number of cells present.…”

Macrophages Coordinate Immune Response to Laser-Induced Injury via Extracellular Traps

“…In line with the literature, our transcriptome analysis of phagocytic cells revealed an increased expression of PAD4. The PAD4 inhibitors in preclinical models of CNS injury, such as choroidal neovascularization and traumatic brain injury (TBI), demonstrated that the level of ETs formation in vivo is closely correlated with local inflammation and pathogenesis (109)(110)(111). Vaibhav et al recently reported that the administration of Cl-amidine led to reduced ET production post-TBI, accompanied by decreased cerebral edema, improved blood flow, and alleviated neurological deficits following the injury (111).…”

The Role of Neutrophil Extracellular Traps in the Outcome of Malignant Epitheliomas: Significance of CA215 Involvement

“…qPCR targets specific NET genes or repetitive DNA sequences to amplify and quantify extracellular DNA. However, it is essential to ensure that NET-derived DNA is accurately differentiated from other sources of DNA [82,[87][88][89][90]. Specific primers for NET-associated DNA sequences include histone-bound DNA fragments, DNA-NE complex, and MPO, which are unique to NETs.…”

“…Specific primers for NET-associated DNA sequences include histone-bound DNA fragments, DNA-NE complex, and MPO, which are unique to NETs. This method allows for a precise quantification of NETs [82,[87][88][89][90].…”

“…This approach provides better insight into the sequential aspects, architecture, or heterogeneity of NET production. However, it is more challenging to analyze and typically requires a well-trained researcher to fully integrate and corelate the data within the experimental or clinical context [81,90,[96][97][98][99]. These assays require a multi-faceted approach.…”