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TWEAK and TNFα, Both TNF Ligand Family Members and Multiple Sclerosis-Related Cytokines, Induce Distinct Gene Response in Human Brain Microvascular Endothelial Cells.

ABSTRACT: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the TNF ligand family involved in various diseases including brain inflammatory pathologies such as multiple sclerosis. It has been demonstrated that TWEAK can induce cerebrovascular permeability in an in vitro model of the blood-brain barrier. The molecular mechanisms playing a role in TWEAK versus TNFα signaling on cerebral microvascular endothelial cells are not well defined. Therefore, we aimed to identify gene expression changes in cultures of human brain microvascular endothelial cells (hCMEC/D3) to address changes initiated by TWEAK exposure. Taken together, our studies highlighted that gene involved in leukocyte extravasation, notably claudin-5, were differentially modulated by TWEAK and TNFα. We identified differential gene expression of hCMEC/D3 cells at three timepoints following TWEAK versus TNFα stimulation and also found distinct modulations of several canonical pathways including the actin cytoskeleton, vascular endothelial growth factor (VEGF), Rho family GTPases, and phosphatase and tensin homolog (PTEN) pathways. To our knowledge, this is the first study to interrogate and compare the effects of TWEAK versus TNFα on gene expression in brain microvascular endothelial cells.

SUBMITTER: Stephan D

PROVIDER: S-EPMC9601571 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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TWEAK and TNFα, Both TNF Ligand Family Members and Multiple Sclerosis-Related Cytokines, Induce Distinct Gene Response in Human Brain Microvascular Endothelial Cells.

Stephan Delphine D Roger Anais A Aghzadi Jehanne J Carmona Sylvie S Picard Christophe C Dales Jean-Philippe JP Desplat-Jégo Sophie S

Genes 20220924 10

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the TNF ligand family involved in various diseases including brain inflammatory pathologies such as multiple sclerosis. It has been demonstrated that TWEAK can induce cerebrovascular permeability in an in vitro model of the blood-brain barrier. The molecular mechanisms playing a role in TWEAK versus TNFα signaling on cerebral microvascular endothelial cells are not well defined. Therefore, we aimed to identify gene expre ...[more]

PMID: 36292599

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Project description:BackgroundVestibular schwannoma (VS) is an intracranial tumor arising from the Schwann cells of the vestibular nerve and is an important cause of sensorineural hearing loss (SNHL) in humans. The mechanisms underlying this SNHL are incompletely understood and currently, there are no drugs FDA approved specifically for VS. This knowledge gap significantly limits the development of effective treatments aimed at preventing, stabilizing, or reversing VS-induced SNHL.MethodsTo identify effector molecules involved in VS-induced SNHL, we analyzed 47 immune-related factors secreted by tumor tissue in over 50 patients with sporadic VS and studied their correlation with preoperative hearing ability and tumor size. The most promising effector molecules were validated in vivo in an anatomically accurate mouse model of VS, and in vitro with mouse fibroblasts (L929) and auditory cell lines representing pro-sensory precursors of hair cells (UB-OC1) and auditory neuroblasts (US-VOT-N33).ResultsWe demonstrated that VS-induced SNHL was linked to increased secretion of TNF-α, IL-2R, CD163, eotaxin, and HGF, while larger tumor size was associated with higher levels of TNF-α, TNF-R2, IL-1α, IFN-α, MIP-1β, and IL-21 secretion. We identified heterogeneity among VS tumors in their capacity to secrete TNF-α. Tumors with high levels of TNF-α secretion released cytokines and chemokines that significantly correlated with poor hearing (TWEAK and eotaxin) or better hearing (LIF, GRO-α, MIP-1α, MIP-3α, and IL-1α). Among these, TWEAK was notably abundant, with levels exceeding those in normal nerve tissue, elevated in patients with non-serviceable hearing and strongly linked to poor hearing in patients with TNF-α high-secreting tumors. In vivo, we demonstrated that VS-secreted factors reach the inner ear, with elevated TNF-α and TWEAK in the perilymph and blood of tumor-bearing mice with impaired hearing. In vitro, TWEAK amplified TNF-α -mediated cytotoxicity in TNF-α sensitive cells (L929) and auditory cell lines (UB-OC1 and US-VOT-N33) at tumor-secreted concentrations.ConclusionThis study provides compelling evidence that VS-secreted TNF-α and TWEAK act synergistically to drive tumor-induced SNHL. Targeting the TNF-α/TWEAK axis presents a promising new avenue for preventing VS-induced SNHL.

Dataset Information

TWEAK and TNFα, Both TNF Ligand Family Members and Multiple Sclerosis-Related Cytokines, Induce Distinct Gene Response in Human Brain Microvascular Endothelial Cells.

Publications

TWEAK and TNFα, Both TNF Ligand Family Members and Multiple Sclerosis-Related Cytokines, Induce Distinct Gene Response in Human Brain Microvascular Endothelial Cells.

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