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Review
. 2023 Feb 17:10:1083242.
doi: 10.3389/fmed.2023.1083242. eCollection 2023.

Neutrophil extracellular traps in central nervous system pathologies: A mini review

Areez Shafqat  1 , Ahmed Noor Eddin  1 , Ghaith Adi  1 , Mohammed Al-Rimawi  1 , Saleha Abdul Rab  1 , Mylia Abu-Shaar  1 , Kareem Adi  1 , Khaled Alkattan  1 , Ahmed Yaqinuddin  1
Affiliations
Review

Neutrophil extracellular traps in central nervous system pathologies: A mini review

Areez Shafqat et al. Front Med (Lausanne). .

Abstract

Neutrophils are the first cells to be recruited to sites of acute inflammation and contribute to host defense through phagocytosis, degranulation and neutrophil extracellular traps (NETs). Neutrophils are rarely found in the brain because of the highly selective blood-brain barrier (BBB). However, several diseases disrupt the BBB and cause neuroinflammation. In this regard, neutrophils and NETs have been visualized in the brain after various insults, including traumatic (traumatic brain injury and spinal cord injury), infectious (bacterial meningitis), vascular (ischemic stroke), autoimmune (systemic lupus erythematosus), neurodegenerative (multiple sclerosis and Alzheimer's disease), and neoplastic (glioma) causes. Significantly, preventing neutrophil trafficking into the central nervous system or NET production in these diseases alleviates brain pathology and improves neurocognitive outcomes. This review summarizes the major studies on the contribution of NETs to central nervous system (CNS) disorders.

Keywords: Alzheimer’s disease; blood-brain barrier; neurodegeneration; neuroinflammation; neutrophil extracellular traps; neutrophils (PMNs); stroke; traumatic brain injury.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
(A) Lytic NETosis describes neutrophil cell death with release of intracellular contents as neutrophil extracellular traps (NETs). By contrast, neutrophils retain viability and phagocytic effector functions after (B) vital and (C) mitochondrial NET formation. Nicotinamide adenine dinucleotide phosphate oxidase activation, reactive oxygen species, neutrophil elastase (NE), myeloperoxidase (MPO), and peptidyl-arginine deaminase-4 (PAD-4) are important cellular mediators of NETs production. NETs can be targeted pharmacologically by preventing their formation (e.g., PAD4 inhibitors, NE inhibitors), accelerating degradation by DNase, or inhibiting specific NET components [e.g., NE inhibitors, matrix metalloproteinase-9 (MMP-9) inhibitors]. Created with BioRender.com.
FIGURE 2
FIGURE 2
Brain injuries of various etiologies cause neutrophil adhesion to the brain microvascular endothelial cells (BMECs) via integrins, namely LFA-1 and VLA-4 integrins, which bind endothelial surface intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule 1, respectively. Adhesion to the BMECs activates neutrophils. Neutrophil adhesion to platelet derived high-mobility group box-1 (HMGB1) through toll-like receptor-4 (TLR4) causes neutrophil activation and intravascular neutrophil extracellular trap (NET) production. NETs comprise neutrophil elastase, citrullinated histone H3, matrix metalloproteinases (MMPs), and cell-free DNA. These NET components increase blood-brain barrier (BBB) permeability through a variety of mechanisms. For instance, MMP-9 degrades type IV collagen of the basal lamina of cerebral blood vessels, compromising blood-brain barrier (BBB) integrity. Intraparenchymal neutrophils also undergo NETosis. The ensuing neuronal damage and microglial cell activation amplify neuroinflammation and cause neuronal loss. Created with Biorender.com.
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