Meningitic Escherichia coli α-hemolysin aggravates blood–brain barrier disruption via targeting TGFβ1-triggered hedgehog signaling

Fu, Jiyang; Li, Liang; Huo, Dong; Yang, Ruicheng; Yang, Bo; Xu, Bin; Yang, Xiaopei; Dai, Menghong; Tan, Chen; Chen, Huanchun; Wang, Xiangru

doi:10.1186/s13041-021-00826-2

Cited by 10 publications

(12 citation statements)

References 46 publications

(58 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The α-hemolysin in meningitic E. coli K1 strain has been demonstrated to reduce ZO-1 expression of hBMEC by inhibiting the TGFβ1-TGFBRII-Smad2/3-Gli1/2 axis . OmpA-mediated meningitic E.…”

Section: Discussionmentioning

confidence: 99%

“… 24 The α-hemolysin in meningitic E. coli K1 strain has been demonstrated to reduce ZO-1 expression of hBMEC by inhibiting the TGFβ1-TGFBRII-Smad2/3-Gli1/2 axis. 25 OmpA-mediated meningitic E. coli adhesion of hBMEC activated PKCα signaling, resulting in β-catenin dissociation from Cadherins, eventually leading to BBB breakdown. 26 In addition, several host molecules have been reported to mediate the enhancement of BBB permeability during E. coli meningitis, such as platelet-derived growth factor B (PDGFB), IL-17A, Snail-1, IL-1β, IL-6, and TNF-α.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Yang,

Chen,

et al. 2024

ACS Infect. Dis.

Self Cite

View full text Add to dashboard Cite

Escherichia coli continues to be the predominant Gram-negative pathogen causing neonatal meningitis worldwide. Inflammatory mediators have been implicated in the pathogenesis of meningitis and are key therapeutic targets. The role of interleukin-22 (IL-22) in various diseases is diverse, with both protective and pathogenic effects. However, little is understood about the mechanisms underlying the damaging effects of IL-22 on the blood−brain barrier (BBB) in E. coli meningitis. We observed that meningitic E. coli infection induced IL-22 expression in the serum and brain of mice. The tight junction proteins (TJPs) components ZO-1, Occludin, and Claudin-5 were degraded in the mouse brain and human brain microvascular endothelial cells (hBMEC) following IL-22 administration. Moreover, the meningitic E. coli-caused increase in BBB permeability in wild-type mice was restored by knocking out IL-22. Mechanistically, IL-22 activated the STAT3-VEGFA signaling cascade in E. coli meningitis, thus eliciting the degradation of TJPs to induce BBB disruption. Our data indicated that IL-22 is an essential host accomplice during E. coli-caused BBB disruption and could be targeted for the therapy of bacterial meningitis.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Yang,

Chen,

et al. 2024

ACS Infect. Dis.

Self Cite

View full text Add to dashboard Cite

show abstract

“…The hBMECs were subsequently used as in vitro model. We additionally tested the effects of IL-17A on TEER value, an important indicator of the monolayer permeability (Fu et al, 2021), by application of ECIS system. The results showed that IL-17A could dose-dependently down-regulate the TEER value of hBMECs monolayer (Figure 2C).…”

Section: Interleukin-17a Promoted the Disruption Of Blood-brain Barri...mentioning

confidence: 99%

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

Chen

et al. 2022

Front. Cell. Neurosci.

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…Astrocytes-derived TGFβ1, and the exogenous recombined TGFβ1 (rTGFβ1) activate transcription factors of HH signaling, Gli1 and Gli2. This noncanonical HH signaling protects mice from death upon meningitic E. coli infection by maintaining BBB integrity [ 21 ]. Consideration of TGFβ1 to modulate the immunity, we presumed that TGFβ1 might also repress the BBB immune reaction while maintaining the BBB integrity.…”

Section: Introductionmentioning

confidence: 99%

TGFβ1-induced hedgehog signaling suppresses the immune response of brain microvascular endothelial cells elicited by meningitic Escherichia coli

Sun,

Yang,

et al. 2024

Cell Commun Signal

Self Cite

View full text Add to dashboard Cite

Background Meningitic Escherichia coli (E. coli) is the major etiological agent of bacterial meningitis, a life-threatening infectious disease with severe neurological sequelae and high mortality. The major cause of central nervous system (CNS) damage and sequelae is the bacterial-induced inflammatory storm, where the immune response of the blood-brain barrier (BBB) is crucial. Methods Western blot, real-time PCR, enzyme-linked immunosorbent assay, immunofluorescence, and dual-luciferase reporter assay were used to investigate the suppressor role of transforming growth factor beta 1 (TGFβ1) in the immune response of brain microvascular endothelial cells elicited by meningitic E. coli. Result In this work, we showed that exogenous TGFβ1 and induced noncanonical Hedgehog (HH) signaling suppressed the endothelial immune response to meningitic E. coli infection via upregulation of intracellular miR-155. Consequently, the increased miR-155 suppressed ERK1/2 activation by negatively regulating KRAS, thereby decreasing IL-6, MIP-2, and E-selectin expression. In addition, the exogenous HH signaling agonist SAG demonstrated promising protection against meningitic E. coli-induced neuroinflammation. Conclusion Our work revealed the effect of TGFβ1 antagonism on E. coli-induced BBB immune response and suggested that activation of HH signaling may be a potential protective strategy for future bacterial meningitis therapy.

show abstract

Meningitic Escherichia coli α-hemolysin aggravates blood–brain barrier disruption via targeting TGFβ1-triggered hedgehog signaling

Cited by 10 publications

References 46 publications

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

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

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

TGFβ1-induced hedgehog signaling suppresses the immune response of brain microvascular endothelial cells elicited by meningitic Escherichia coli

Contact Info

Product

Resources

About