Chronic inflammation of middle ear cholesteatoma promotes its recurrence via a paracrine mechanism
Abstract Background Cholesteatoma disease is an expanding lesion in the middle ear. Hearing loss and facial paralysis alongside with other intracranial complications are found. No pharmaceutical treatment is available today and recurrence after surgical extraction occurs. We investigated possible TL...
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| Format: | Article |
| Language: | English |
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BMC
2021-02-01
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| Series: | Cell Communication and Signaling |
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| Online Access: | https://doi.org/10.1186/s12964-020-00690-y |
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| author | Matthias Schürmann Felix Oppel Senyao Shao Verena Volland-Thurn Christian Kaltschmidt Barbara Kaltschmidt Lars-Uwe Scholtz Holger Sudhoff |
| author_facet | Matthias Schürmann Felix Oppel Senyao Shao Verena Volland-Thurn Christian Kaltschmidt Barbara Kaltschmidt Lars-Uwe Scholtz Holger Sudhoff |
| author_sort | Matthias Schürmann |
| collection | DOAJ |
| description | Abstract Background Cholesteatoma disease is an expanding lesion in the middle ear. Hearing loss and facial paralysis alongside with other intracranial complications are found. No pharmaceutical treatment is available today and recurrence after surgical extraction occurs. We investigated possible TLR4-based mechanisms promoting recurrence and explore possible treatments strategies. Methods We isolated fibroblasts and epidermal stem cells from cholesteatoma tissue and healthy auditory canal skin. Subsequently, their expression under standard culture conditions and after stimulation with LPS was investigated by RT-qPCR. Cell metabolism and proliferation were analysed upon LPS treatment, with and without TLR4 antagonist. An indirect co-culture of fibroblasts and epidermal stem cells isolated from cholesteatoma tissue was utilized to monitor epidermal differentiation upon LPS treatment by RT-qPCR and immunocytochemistry. Results Under standard culture conditions, we detected a tissue-independent higher expression of IL-1β and IL-8 in stem cells, an upregulation of KGF and IGF-2 in both cell types derived from cholesteatoma and higher expression of TLR4 in stem cells derived from cholesteatoma tissue. Upon LPS challenge, we could detect a significantly higher expression of IL-1α, IL-1β, IL-6 and IL-8 in stem cells and of TNF-a, GM-CSF and CXCL-5 in stem cells and fibroblasts derived from cholesteatoma. The expression of the growth factors KGF, EGF, EREG, IGF-2 and HGF was significantly higher in fibroblasts, particularly when derived from cholesteatoma. Upon treatment with LPS the metabolism was elevated in stem cells and fibroblasts, proliferation was only enhanced in fibroblasts derived from cholesteatoma. This could be reversed by the treatment with a TLR4 antagonist. The cholesteatoma fibroblasts could be triggered by LPS to promote the epidermal differentiation of the stem cells, while no LPS treatment or LPS treatment without the presence of fibroblasts did not result in such a differentiation. Conclusion We propose that cholesteatoma recurrence is based on TLR4 signalling imprinted in the cholesteatoma cells. It induces excessive inflammation of stem cells and fibroblasts, proliferation of perimatrix fibroblasts and the generation of epidermal cells from stem cells thru paracrine signalling by fibroblasts. Treatment of the operation site with a TLR4 antagonist might reduce the chance of cholesteatoma recurrence. Video Abstract |
| first_indexed | 2024-12-14T00:06:28Z |
| format | Article |
| id | doaj.art-1d4a878031d64d08af9168e7eddfeb5a |
| institution | Directory Open Access Journal |
| issn | 1478-811X |
| language | English |
| last_indexed | 2024-12-14T00:06:28Z |
| publishDate | 2021-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj.art-1d4a878031d64d08af9168e7eddfeb5a2022-12-21T23:26:00ZengBMCCell Communication and Signaling1478-811X2021-02-0119111510.1186/s12964-020-00690-yChronic inflammation of middle ear cholesteatoma promotes its recurrence via a paracrine mechanismMatthias Schürmann0Felix Oppel1Senyao Shao2Verena Volland-Thurn3Christian Kaltschmidt4Barbara Kaltschmidt5Lars-Uwe Scholtz6Holger Sudhoff7Department of Otolaryngology, Head and Neck Surgery, Medical School OWL Campus Klinikum Bielefeld, Bielefeld UniversityDepartment of Otolaryngology, Head and Neck Surgery, Medical School OWL Campus Klinikum Bielefeld, Bielefeld UniversityDepartment of Otolaryngology, Head and Neck Surgery, Medical School OWL Campus Klinikum Bielefeld, Bielefeld UniversityDepartment of Otolaryngology, Head and Neck Surgery, Medical School OWL Campus Klinikum Bielefeld, Bielefeld UniversityDepartment of Cell Biology, Bielefeld UniversityDepartment of Cell Biology, Bielefeld UniversityDepartment of Otolaryngology, Head and Neck Surgery, Medical School OWL Campus Klinikum Bielefeld, Bielefeld UniversityDepartment of Otolaryngology, Head and Neck Surgery, Medical School OWL Campus Klinikum Bielefeld, Bielefeld UniversityAbstract Background Cholesteatoma disease is an expanding lesion in the middle ear. Hearing loss and facial paralysis alongside with other intracranial complications are found. No pharmaceutical treatment is available today and recurrence after surgical extraction occurs. We investigated possible TLR4-based mechanisms promoting recurrence and explore possible treatments strategies. Methods We isolated fibroblasts and epidermal stem cells from cholesteatoma tissue and healthy auditory canal skin. Subsequently, their expression under standard culture conditions and after stimulation with LPS was investigated by RT-qPCR. Cell metabolism and proliferation were analysed upon LPS treatment, with and without TLR4 antagonist. An indirect co-culture of fibroblasts and epidermal stem cells isolated from cholesteatoma tissue was utilized to monitor epidermal differentiation upon LPS treatment by RT-qPCR and immunocytochemistry. Results Under standard culture conditions, we detected a tissue-independent higher expression of IL-1β and IL-8 in stem cells, an upregulation of KGF and IGF-2 in both cell types derived from cholesteatoma and higher expression of TLR4 in stem cells derived from cholesteatoma tissue. Upon LPS challenge, we could detect a significantly higher expression of IL-1α, IL-1β, IL-6 and IL-8 in stem cells and of TNF-a, GM-CSF and CXCL-5 in stem cells and fibroblasts derived from cholesteatoma. The expression of the growth factors KGF, EGF, EREG, IGF-2 and HGF was significantly higher in fibroblasts, particularly when derived from cholesteatoma. Upon treatment with LPS the metabolism was elevated in stem cells and fibroblasts, proliferation was only enhanced in fibroblasts derived from cholesteatoma. This could be reversed by the treatment with a TLR4 antagonist. The cholesteatoma fibroblasts could be triggered by LPS to promote the epidermal differentiation of the stem cells, while no LPS treatment or LPS treatment without the presence of fibroblasts did not result in such a differentiation. Conclusion We propose that cholesteatoma recurrence is based on TLR4 signalling imprinted in the cholesteatoma cells. It induces excessive inflammation of stem cells and fibroblasts, proliferation of perimatrix fibroblasts and the generation of epidermal cells from stem cells thru paracrine signalling by fibroblasts. Treatment of the operation site with a TLR4 antagonist might reduce the chance of cholesteatoma recurrence. Video Abstracthttps://doi.org/10.1186/s12964-020-00690-yCholesteatomaInflammationTLR4Stem cellsCholesteatoma recurrence |
| spellingShingle | Matthias Schürmann Felix Oppel Senyao Shao Verena Volland-Thurn Christian Kaltschmidt Barbara Kaltschmidt Lars-Uwe Scholtz Holger Sudhoff Chronic inflammation of middle ear cholesteatoma promotes its recurrence via a paracrine mechanism Cell Communication and Signaling Cholesteatoma Inflammation TLR4 Stem cells Cholesteatoma recurrence |
| title | Chronic inflammation of middle ear cholesteatoma promotes its recurrence via a paracrine mechanism |
| title_full | Chronic inflammation of middle ear cholesteatoma promotes its recurrence via a paracrine mechanism |
| title_fullStr | Chronic inflammation of middle ear cholesteatoma promotes its recurrence via a paracrine mechanism |
| title_full_unstemmed | Chronic inflammation of middle ear cholesteatoma promotes its recurrence via a paracrine mechanism |
| title_short | Chronic inflammation of middle ear cholesteatoma promotes its recurrence via a paracrine mechanism |
| title_sort | chronic inflammation of middle ear cholesteatoma promotes its recurrence via a paracrine mechanism |
| topic | Cholesteatoma Inflammation TLR4 Stem cells Cholesteatoma recurrence |
| url | https://doi.org/10.1186/s12964-020-00690-y |
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