Deciphering the Contribution of Human Meningothelial Cells to the Inflammatory and Antimicrobial Response at the Meninges

Royer, Pierre‐Joseph; Rogers, A. J.; Wooldridge, Karl G.; Tighe, Patrick J.; Mahdavi, Jafar; Rittig, Michael; Ala’Aldeen, Dlawer A. A.

doi:10.1128/iai.00477-13

Cited by 15 publications

(8 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…NF-κB is tightly controlled by negative feedback loops mediated primarily by IκB, leading to oscillatory responses, in which NF-κB shuttles between the cytoplasm and nucleus with the period of about 100 min [ 20 ]. Comparing to other reports [ 34 ], the steady decrease of IκB over the period of 12h of infection was surprising. Meningococcal infection may interact with other components of NF-κB signaling pathway including IKK complex and/or A20/TNFAIP3 to attenuate the negative feedback loop mediated by IκB [ 35 , 36 , 37 , 38 ] although cell lines and bacterial strains used in this study may account for these differences.…”

Section: Discussioncontrasting

confidence: 95%

Hyperinvasive Meningococci Induce Intra-nuclear Cleavage of the NF-κB Protein p65/RelA by Meningococcal IgA Protease

et al. 2015

View full text Add to dashboard Cite

Differential modulation of NF-κB during meningococcal infection is critical in innate immune response to meningococcal disease. Non-invasive isolates of Neisseria meningitidis provoke a sustained NF-κB activation in epithelial cells. However, the hyperinvasive isolates of the ST-11 clonal complex (ST-11) only induce an early NF-κB activation followed by a sustained activation of JNK and apoptosis. We show that this temporal activation of NF-κB was caused by specific cleavage at the C-terminal region of NF-κB p65/RelA component within the nucleus of infected cells. This cleavage was mediated by the secreted 150 kDa meningococcal ST-11 IgA protease carrying nuclear localisation signals (NLS) in its α-peptide moiety that allowed efficient intra-nuclear transport. In a collection of non-ST-11 healthy carriage isolates lacking NLS in the α-peptide, secreted IgA protease was devoid of intra-nuclear transport. This part of iga polymorphism allows non-invasive isolates lacking NLS, unlike hyperinvasive ST-11 isolates of N. meningitides habouring NLS in their α-peptide, to be carried asymptomatically in the human nasopharynx through selective eradication of their ability to induce apoptosis in infected epithelial cells.

show abstract

Section: Discussioncontrasting

confidence: 95%

Hyperinvasive Meningococci Induce Intra-nuclear Cleavage of the NF-κB Protein p65/RelA by Meningococcal IgA Protease

et al. 2015

View full text Add to dashboard Cite

show abstract

“…This effect is mediated by the inhibition of IL6 secretion [ 37 ]. Meningiomas are believed to develop from meningiothelial cells that have several functions, including participating in immune response and IL6 secretion [ 38 ]. We hypothesize that IL6 secretion from meningioma cells could be involved in the tumorigenesis of meningiomas.…”

Section: Discussionmentioning

confidence: 99%

Pasireotide is more effective than octreotide, alone or combined with everolimus on human meningiomain vitro

et al. 2017

View full text Add to dashboard Cite

Pasireotide is a somatostatin analog (SSA) that targets somatostatin receptor subtype 1 (SST1), SST2, SST3, and SST5 with a high affinity. Pasireotide has a better antisecretory effect in acromegaly, Cushing's disease, and neuroendocrine tumors than octreotide. In this study, we compared the effects of pasireotide to those of octreotide in vitro on meningioma primary cell cultures, both alone and in combination with the mTOR inhibitor everolimus. Significant mRNA expression levels of SST1, SST2, and SST5 were observed in 40.5%, 100%, and 35% of meningioma samples, respectively. Pasireotide had a significantly stronger inhibitory effect on cell proliferation than octreotide. The effect of pasireotide, but not of octreotide, was significantly stronger in the group expressing the highest level of SST1 mRNA. Combined treatment with pasireotide and everolimus induced a higher reduction in cell viability than that with octreotide plus everolimus. Moreover, pasireotide decreased Akt phosphorylation and reversed everolimus-induced Akt hyperphosphorylation to a higher degree than octreotide. Using 4E-BP1 siRNA (si4E-BP), we demonstrated that 4E-BP1 protein silencing significantly reversed the response to everolimus, both alone and in combination with SSAs. Moreover, si4E-BP completely reversed the inhibition of cyclin D1 expression level and the increase in p27kip1 induced by SSAs, both alone and in combination with everolimus. Our results strongly support the need for further studies on the combination of pasireotide and everolimus in medical therapy for meningiomas.

show abstract

“…In agreement with these studies, we detected production of TNFα, IL8, and IL6 by HIBCPP cells after exposure to Nm . It should be noted that the amount of IL6 produced by HIBCPP cells is quite low, especially when compared to expression levels reached in meningothelial meningioma cells [ 54 , 55 ]. These differences can be possibly attributed to the distinct cell types used in the experiments and to the fact that HIBCPP cells do not necessarily mirror the amounts of IL6 produced by CP epithelial cells in vivo .…”

Section: Discussionmentioning

confidence: 99%

Neisseria meningitidiselicits a pro-inflammatory response involving IκBζ in a human blood-cerebrospinal fluid barrier model

Borkowski

Steinmann

et al. 2014

J Neuroinflammation

View full text Add to dashboard Cite

BackgroundThe human-specific, Gram-negative bacterium Neisseria meningitidis (Nm) is a leading cause of bacterial meningitis worldwide. The blood-cerebrospinal fluid barrier (BCSFB), which is constituted by the epithelial cells of the choroid plexus (CP), has been suggested as one of the potential entry sites of Nm into the CSF and can contribute to the inflammatory response during infectious diseases of the brain. Toll-like receptors (TLRs) are involved in mediating signal transduction caused by the pathogens.MethodsUsing a recently established in vitro model of the human BCSFB based on human malignant CP papilloma (HIBCPP) cells we investigated the cellular response of HIBCPP cells challenged with the meningitis-causing Nm strain, MC58, employing transcriptome and RT-PCR analysis, cytokine bead array, and enzyme-linked immunosorbent assay (ELISA). In comparison, we analyzed the answer to the closely related unencapsulated carrier isolate Nm α14. The presence of TLRs in HIBCPP and their role during signal transduction caused by Nm was studied by RT-PCR and the use of specific agonists and mutant bacteria.ResultsWe observed a stronger transcriptional response after infection with strain MC58, in particular with its capsule-deficient mutant MC58siaD−, which correlated with bacterial invasion levels. Expression evaluation and Gene Set Enrichment Analysis pointed to a NFκB-mediated pro-inflammatory immune response involving up-regulation of the transcription factor IκBζ. Infected cells secreted significant levels of pro-inflammatory chemokines and cytokines, including, among others, IL8, CXCL1-3, and the IκBζ target gene product IL6. The expression profile of pattern recognition receptors in HIBCPP cells and the response to specific agonists indicates that TLR2/TLR6, rather than TLR4 or TLR2/TLR1, is involved in the cellular reaction following Nm infection.ConclusionsOur data show that Nm can initiate a pro-inflammatory response in human CP epithelial cells probably involving TLR2/TLR6 signaling and the transcriptional regulator IκBζ.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-014-0163-x) contains supplementary material, which is available to authorized users.

show abstract

Deciphering the Contribution of Human Meningothelial Cells to the Inflammatory and Antimicrobial Response at the Meninges

Cited by 15 publications

References 39 publications

Hyperinvasive Meningococci Induce Intra-nuclear Cleavage of the NF-κB Protein p65/RelA by Meningococcal IgA Protease

Hyperinvasive Meningococci Induce Intra-nuclear Cleavage of the NF-κB Protein p65/RelA by Meningococcal IgA Protease

Pasireotide is more effective than octreotide, alone or combined with everolimus on human meningiomain vitro

Neisseria meningitidiselicits a pro-inflammatory response involving IκBζ in a human blood-cerebrospinal fluid barrier model

Contact Info

Product

Resources

About