Cargando…
Stem Cell-Induced Inflammation in Cholesteatoma Is Inhibited by the TLR4 Antagonist LPS-RS
Cholesteatoma is a severe non-cancerous lesion of the middle ear characterized by massive inflammation, tissue destruction, and an abnormal growth of keratinized squamous epithelium. We recently demonstrated the presence of pathogenic stem cells within cholesteatoma tissue, unfortunately their poten...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017370/ https://www.ncbi.nlm.nih.gov/pubmed/31947538 http://dx.doi.org/10.3390/cells9010199 |
_version_ | 1783497183853543424 |
---|---|
author | Schürmann, Matthias Greiner, Johannes F. W. Volland-Thurn, Verena Oppel, Felix Kaltschmidt, Christian Sudhoff, Holger Kaltschmidt, Barbara |
author_facet | Schürmann, Matthias Greiner, Johannes F. W. Volland-Thurn, Verena Oppel, Felix Kaltschmidt, Christian Sudhoff, Holger Kaltschmidt, Barbara |
author_sort | Schürmann, Matthias |
collection | PubMed |
description | Cholesteatoma is a severe non-cancerous lesion of the middle ear characterized by massive inflammation, tissue destruction, and an abnormal growth of keratinized squamous epithelium. We recently demonstrated the presence of pathogenic stem cells within cholesteatoma tissue, unfortunately their potential roles in regulating disease-specific chronic inflammation remain poorly understood. In the presented study, we utilized our established human in vitro cholesteatoma stem cell model for treatments with lipopolysaccharides (LPS), tumor necrosis factor α (TNFα), and the TLR4-antagonist LPS from R. sphaeroides (LPS-RS) followed by qPCR, western blot, and immunocytochemistry. Middle ear cholesteatoma stem cells (ME-CSCs) showed a significantly increased expression of TLR4 accompanied by a significantly enhanced LPS-dependent pro-inflammatory gene expression pattern of TNFα, IL-1α, IL-1ß, IL-6, and IL-8 compared to non-pathogenic control cells. LPS-dependent pro-inflammatory gene expression in ME-CSCs was driven by an enhanced activity of NF-κB p65 leading to a TNFα-mediated feed-forward-loop of pro-inflammatory NF-κB target gene expression. Functional inactivation of TLR4 via the TLR4-antagonist LPS-RS blocked chronic inflammation in ME-CSCs, resulting in a nearly complete loss of IL-1ß, IL-6, and TNFα expression. In summary, we determined that ME-CSCs mediate the inflammatory environment of cholesteatoma via TLR4-mediated NF-κB-signaling, suggesting a distinct role of ME-CSCs as drivers of cholesteatoma progression and TLR4 on ME-CSCs as a therapeutic target. |
format | Online Article Text |
id | pubmed-7017370 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-70173702020-03-04 Stem Cell-Induced Inflammation in Cholesteatoma Is Inhibited by the TLR4 Antagonist LPS-RS Schürmann, Matthias Greiner, Johannes F. W. Volland-Thurn, Verena Oppel, Felix Kaltschmidt, Christian Sudhoff, Holger Kaltschmidt, Barbara Cells Article Cholesteatoma is a severe non-cancerous lesion of the middle ear characterized by massive inflammation, tissue destruction, and an abnormal growth of keratinized squamous epithelium. We recently demonstrated the presence of pathogenic stem cells within cholesteatoma tissue, unfortunately their potential roles in regulating disease-specific chronic inflammation remain poorly understood. In the presented study, we utilized our established human in vitro cholesteatoma stem cell model for treatments with lipopolysaccharides (LPS), tumor necrosis factor α (TNFα), and the TLR4-antagonist LPS from R. sphaeroides (LPS-RS) followed by qPCR, western blot, and immunocytochemistry. Middle ear cholesteatoma stem cells (ME-CSCs) showed a significantly increased expression of TLR4 accompanied by a significantly enhanced LPS-dependent pro-inflammatory gene expression pattern of TNFα, IL-1α, IL-1ß, IL-6, and IL-8 compared to non-pathogenic control cells. LPS-dependent pro-inflammatory gene expression in ME-CSCs was driven by an enhanced activity of NF-κB p65 leading to a TNFα-mediated feed-forward-loop of pro-inflammatory NF-κB target gene expression. Functional inactivation of TLR4 via the TLR4-antagonist LPS-RS blocked chronic inflammation in ME-CSCs, resulting in a nearly complete loss of IL-1ß, IL-6, and TNFα expression. In summary, we determined that ME-CSCs mediate the inflammatory environment of cholesteatoma via TLR4-mediated NF-κB-signaling, suggesting a distinct role of ME-CSCs as drivers of cholesteatoma progression and TLR4 on ME-CSCs as a therapeutic target. MDPI 2020-01-14 /pmc/articles/PMC7017370/ /pubmed/31947538 http://dx.doi.org/10.3390/cells9010199 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Schürmann, Matthias Greiner, Johannes F. W. Volland-Thurn, Verena Oppel, Felix Kaltschmidt, Christian Sudhoff, Holger Kaltschmidt, Barbara Stem Cell-Induced Inflammation in Cholesteatoma Is Inhibited by the TLR4 Antagonist LPS-RS |
title | Stem Cell-Induced Inflammation in Cholesteatoma Is Inhibited by the TLR4 Antagonist LPS-RS |
title_full | Stem Cell-Induced Inflammation in Cholesteatoma Is Inhibited by the TLR4 Antagonist LPS-RS |
title_fullStr | Stem Cell-Induced Inflammation in Cholesteatoma Is Inhibited by the TLR4 Antagonist LPS-RS |
title_full_unstemmed | Stem Cell-Induced Inflammation in Cholesteatoma Is Inhibited by the TLR4 Antagonist LPS-RS |
title_short | Stem Cell-Induced Inflammation in Cholesteatoma Is Inhibited by the TLR4 Antagonist LPS-RS |
title_sort | stem cell-induced inflammation in cholesteatoma is inhibited by the tlr4 antagonist lps-rs |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017370/ https://www.ncbi.nlm.nih.gov/pubmed/31947538 http://dx.doi.org/10.3390/cells9010199 |
work_keys_str_mv | AT schurmannmatthias stemcellinducedinflammationincholesteatomaisinhibitedbythetlr4antagonistlpsrs AT greinerjohannesfw stemcellinducedinflammationincholesteatomaisinhibitedbythetlr4antagonistlpsrs AT vollandthurnverena stemcellinducedinflammationincholesteatomaisinhibitedbythetlr4antagonistlpsrs AT oppelfelix stemcellinducedinflammationincholesteatomaisinhibitedbythetlr4antagonistlpsrs AT kaltschmidtchristian stemcellinducedinflammationincholesteatomaisinhibitedbythetlr4antagonistlpsrs AT sudhoffholger stemcellinducedinflammationincholesteatomaisinhibitedbythetlr4antagonistlpsrs AT kaltschmidtbarbara stemcellinducedinflammationincholesteatomaisinhibitedbythetlr4antagonistlpsrs |