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

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Copyright © 2023 Shafqat, Noor Eddin, Adi, Al-Rimawi, Abdul Rab, Abu-Shaar, Adi, Alkattan and Yaqinuddin.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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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.