Meningitic Escherichia coli-Induced Interleukin-17A Facilitates Blood–Brain Barrier Disruption via Inhibiting Proteinase 3/Protease-Activated Receptor 2 Axis

Abstract

Bacterial meningitis is a life-threatening infectious disease with high morbidity and mortality worldwide, among which meningitic Escherichia coli is a common Gram-negative pathogenic bacterium causing meningitis. It can penetrate the blood–brain barrier (BBB), invoke local inflammatory responses and consequently disrupt the integrity of the BBB. Interleukin-17A (IL-17A) is recognized as a pro-inflammatory cytokine that is released during meningitic E. coli infection. It has been reported that IL-17A is involved in several pathological tissue injuries. However, the function of IL-17A in BBB breakdown remains rarely discussed. Here, our study found that E. coli-induced IL-17A led to the degradation of tight junction proteins (TJs) and adherens junction proteins (AJs) in human brain microvascular endothelial cells (hBMECs) through inhibiting protease proteinase 3 (PRTN3)/protease-activated receptor 2 (PAR-2) axis, thus increasing the permeability of BBB. In summary, this study uncovered the involvement of IL-17A in regulating BBB integrity and proposed a novel regulatory mechanism, which could be potential therapeutic targets of E. coli meningitis.

Interleukin-22 Contributes to Blood–Brain Barrier Disruption via STAT3/VEGFA Activation in Escherichia coli Meningitis

“…A recent study found that meningitic E. coli-induced IL-17A significantly reduced hBMEC TJPs expression at the post-transcriptional level by inhibiting the proteinase 3/protease-activated receptor 2 axis, thus augmenting endothelial permeability and disrupting BBB integrity . It has been demonstrated that overexpression of transcription factor Snail-1 destroys the top complex of vascular endothelial cells .…”

“… 9 A recent study found that meningitic E. coli -induced IL-17A significantly reduced hBMEC TJPs expression at the post-transcriptional level by inhibiting the proteinase 3/protease-activated receptor 2 axis, thus augmenting endothelial permeability and disrupting BBB integrity. 27 It has been demonstrated that overexpression of transcription factor Snail-1 destroys the top complex of vascular endothelial cells. 28 Meningitic E. coli -infected hBMEC were found to increase the expression of Snail-1 that mediated the degradation of ZO-1, Occludin, and Claudin-5, and disrupted endothelial barrier integrity.…”

Zonulin as a Potential Therapeutic Target in Microbiota-Gut-Brain Axis Disorders: Encouraging Results and Emerging Questions

“…In contrast, inhibition of the PAR 2 pathway by GB88 in lung epithelial cells [ 235 ] or using I-191 in arterial endothelial cells [ 236 ] moderated actin rearrangement and TJ disruption and reduced the permeability of the cellular monolayers. Moreover, a non-peptidic PAR 2 ligand, the full agonist AC-55541, ameliorated the IL-17-induced loss of epithelial resistance in brain microvascular endothelial cells [ 237 ].…”