Middle ear cholesteatoma (MEC) is a destructive and locally invasive ulcerated lesion in the middle ear driven by inflammation which occurs in 10 out of 100,000 people annually. Surgical extraction/excision is the only treatment strategy available and recurrence is high (up to 40% after ten years), therefore developing the first pharmaceutical treatments for MEC is desperately required. This review is focused on the connections between inflammation and MEC pathogenesis. These connections can be used as attack points for pharmaceuticals. For this we summarized the results of research undertaken over the last 30 + years. MEC pathogenesis can be described by specific inflammatory dysregulation already known from arthritis, Crohn’s disease or multiple sclerosis. A hallmark of this dysregulation are positive feedback loops of the inflammation further amplifying itself in a vicious circle-like manner. We have identified over one hundred drugs which are already used in clinic to treat other inflammatory diseases, and could potentially be repurposed to treat MEC. To improve and expedite clinical success rates, we applied certain criteria based on our literature searches and condensed these drugs down to the 13 top drugs. We hope the review will serve as groundwork for the primary goal, which is to provide potential pharmaceutical therapies to MEC patients for the first time in history.
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Affiliation(s)
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Cited by Other Article(s) |
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1
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Patel TR, Welch CM. The Science of Cholesteatoma. Otolaryngol Clin North Am 2025; 58:1-27. [PMID: 39353746 DOI: 10.1016/j.otc.2024.07.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/04/2024]
Abstract
Cholesteatoma is a potential end-stage outcome of chronic ear infections that can result in the destruction of temporal bone structures with potential resultant hearing loss, vertigo, and intracranial infectious complications. There is currently no treatment apart from surgery for this condition, and despite years of study, the histopathogenesis of this disease remains poorly understood. This review is intended to summarize our accumulated knowledge of the mechanisms of cholesteatoma development and the underlying molecular biology. Attention will be directed particularly to recent developments, covering many potential pharmacologic targets that could be used to treat this disease in the future.
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Affiliation(s)
- Tirth R Patel
- Division of Otology/Neurotology-Skull Base Surgery, Department of Otolaryngology-Head and Neck Surgery, University of Michigan, 1500 Medical Center Drive, Ann Arbor, MI 48109, USA
| | - Christopher M Welch
- Division of Otology/Neurotology-Skull Base Surgery, Department of Otolaryngology-Head and Neck Surgery, University of Michigan, 1500 Medical Center Drive, Ann Arbor, MI 48109, USA.
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Song ZN, Cheng Y, Wang DD, Li MJ, Zhao XR, Li FW, Liu Z, Zhu XR, Jia XD, Wang YF, Liang FF. Whole exome sequencing identifies risk variants associated with intracranial epidermoid cyst deterioration: A case report. World J Clin Oncol 2024; 15:1428-1434. [PMID: 39582614 PMCID: PMC11514425 DOI: 10.5306/wjco.v15.i11.1428] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 09/11/2024] [Accepted: 09/25/2024] [Indexed: 10/14/2024] Open
Abstract
BACKGROUND Intracranial epidermoid cyst (IEC) transformation to malignant squamous cell carcinoma (SCC) is extremely rare, and its etiology is yet unknown. Currently, SCC is treated by performing surgery, followed by a combination of radiotherapy and chemotherapy. It is crucial to identify efficient and trustworthy therapeutic targets for SCC to improve its diagnosis, prognosis, and treatment. CASE SUMMARY In this study, we report the case of a 47-year-old female patient with SCC, which progressed from IEC in the left internal capsule region. The patient was sought treatment at our hospital for severe diplopic vision, accompanied with speech disorder and memory loss. Based on the clinical and postoperative pathology, this patient was finally diagnosed with SCC. To identify disease-causing variants, whole exome sequencing (WES) was performed on the proband. WES revealed two pathogenic missense mutations on Gap junction protein beta 2 (GJB2) (c.257C>T) and Toll-like receptor 2 (TLR2) (c.1039A>G), respectively. CONCLUSION This study provided the first clinical evidence for demonstrating the role of GJB2 and TLR2 in IEC development and treatment. We further confirmed WES as a robust and reliable technique for underlying rare and complex disease-related genetic factor identification.
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Affiliation(s)
- Zhao-Na Song
- Joint Laboratory for Translational Medicine Research, Liaocheng People's Hospital, Liaocheng 252000, Shandong Province, China
| | - Yan Cheng
- Joint Laboratory for Translational Medicine Research, Liaocheng People's Hospital, Liaocheng 252000, Shandong Province, China
| | - Dan-Dan Wang
- Harbin Genars Technology Co., Ltd., Harbin 150060, Heilongjiang Province, China
| | - Ming-Jun Li
- Department of Radiotherapy, Liaocheng People's Hospital, Liaocheng 252000, Shandong Province, China
| | - Xiang-Rong Zhao
- Department of Radiotherapy, Liaocheng People's Hospital, Liaocheng 252000, Shandong Province, China
| | - Fa-Wang Li
- Department of Medical laboratory, Qilu Hospital of Shandong University Dezhou Hospital, Dezhou 253600, Shandong Province, China
| | - Zhen Liu
- Harbin Genars Technology Co., Ltd., Harbin 150060, Heilongjiang Province, China
| | - Xiao-Ru Zhu
- Harbin Genars Technology Co., Ltd., Harbin 150060, Heilongjiang Province, China
| | - Xiao-Dong Jia
- Joint Laboratory for Translational Medicine Research, Liaocheng People's Hospital, Liaocheng 252000, Shandong Province, China
| | - Yu-Fang Wang
- Department of Radiotherapy, Liaocheng People's Hospital, Liaocheng 252000, Shandong Province, China
| | - Feng-Fan Liang
- Department of Radiotherapy, Liaocheng People's Hospital, Liaocheng 252000, Shandong Province, China
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Schürmann M, Goon P, Sudhoff H. Review of potential medical treatments for middle ear cholesteatoma. Cell Commun Signal 2022; 20:148. [PMID: 36123729 PMCID: PMC9487140 DOI: 10.1186/s12964-022-00953-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 08/05/2022] [Indexed: 11/15/2022] Open
Abstract
Middle ear cholesteatoma (MEC), is a destructive, and locally invasive lesion in the middle ear driven by inflammation with an annual incidence of 10 per 100,000. Surgical extraction/excision remains the only treatment strategy available and recurrence is high (up to 40%), therefore developing the first pharmaceutical treatments for MEC is desperately required. This review was targeted at connecting the dysregulated inflammatory network of MEC to pathogenesis and identification of pharmaceutical targets. We summarized the numerous basic research endeavors undertaken over the last 30+ years to identify the key targets in the dysregulated inflammatory pathways and judged the level of evidence for a given target if it was generated by in vitro, in vivo or clinical experiments. MEC pathogenesis was found to be connected to cytokines characteristic for Th1, Th17 and M1 cells. In addition, we found that the inflammation created damage associated molecular patterns (DAMPs), which further promoted inflammation. Similar positive feedback loops have already been described for other Th1/Th17 driven inflammatory diseases (arthritis, Crohn’s disease or multiple sclerosis). A wide-ranging search for molecular targeted therapies (MTT) led to the discovery of over a hundred clinically approved drugs already applied in precision medicine. Based on exclusion criteria designed to enable fast translation as well as efficacy, we condensed the numerous MTTs down to 13 top drugs. The review should serve as groundwork for the primary goal, which is to provide potential pharmaceutical therapies to MEC patients for the first time in history.
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Video Abstract
- Matthias Schürmann
- Department of Otolaryngology, Head and Neck Surgery, Universität Bielefeld, Teutoburger Str. 50, 33604, Bielefeld, Germany
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- Peter Goon
- Department of Otolaryngology, Head and Neck Surgery, Universität Bielefeld, Teutoburger Str. 50, 33604, Bielefeld, Germany.,Department of Medicine, National University of Singapore, and National University Health System, Singapore, Singapore
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- Holger Sudhoff
- Department of Otolaryngology, Head and Neck Surgery, Universität Bielefeld, Teutoburger Str. 50, 33604, Bielefeld, Germany.
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Nitric Oxide Is Locally Produced in the Human Middle Ear and Is Reduced by Acquired Cholesteatoma.
Otol Neurotol 2021;
43:e198-e204. [PMID:
34699401 DOI:
10.1097/mao.0000000000003395]
[Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE
To find out if nitric oxide (NO) can be locally produced in the middle ear and if chronic otitis media (COM) and acquired cholesteatoma affect the production.
DESIGN
Case-control study.
SETTING
Two tertiary-referral hospitals.
PATIENTS
Gaseous NO from 11 patients with unilateral perforations or grommet openings was measured with chemiluminescence. Middle ear mucosa from 48 patients with COM and 26 patients with cholesteatoma was investigated.
MAIN OUTCOME MEASURES
Detection of NO. Expression of nitric oxide synthase (NOS) mRNA, in mucosa from COM, cholesteatoma and healthy controls, quantified using polymerase chain reaction.
RESULTS
The gaseous NO from ears with a unilateral tympanic membrane perforation or a grommet was higher (9 ± 3 ppb, n = 11) than among the controls (4 ± 1 ppb, n = 11, p = 0.04). Lower levels of eNOS (2.64 ± 0.86 mol/100,000 mol ACTB) were detected in the pooled samples from the COM group (n = 48), compared with the control group (140.48 ± 92 mol/100,000 mol ACTB, n = 45, p = 0.010). In the cholesteatoma group (n = 26), a lower expression of nNOS (5.78 × 10-6 ± 1.13 × 10-6 ΔCt) was found in comparison with the controls (1.23 × 10-4 ± 3.18 × 10-5 ΔCt, n = 15, p = 0.011).
CONCLUSIONS
NO is likely a natural and permanent part of the gas mixture in the human middle ear. The presence of NOS enzymes in the middle ear mucosa indicates an ongoing NO production and the reduction of NOS in ears with cholesteatoma, and pooled samples from ears with COM, suggest a role for locally produced NO in middle ear disease.
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Leichtle A, Leffers D, Daerr MG, Draf C, Kurabi A, Ryan AF, Rupp J, Bruchhage KL. [Immunomodulation in Cholesteatoma].
Laryngorhinootologie 2021;
101:310-319. [PMID:
34233375 DOI:
10.1055/a-1516-4447]
[Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
INTRODUCTION
The etiopathogenesis of chronic otitis media epitympanalis/cholesteatoma and its proliferative destructive course with possible complications such as destruction of bony structures with hearing loss, vestibular dysfunction, facial nerve paralysis and intracranial complications are still unexplained. Surgery is still the way to go. New studies are increasingly looking at the innate immune system.
METHODS
Our studies were carried out in a mouse model in WT mice and immundeficient KO-mice, as well as in cholestatoma and healthy ear canal skin and middle ear tissue, which was removed during ear surgery. The expression analyses were carried out at the gene and protein level using TNF as the major target for therapy evaluation. By means of TUNEL staining and immunohistochemistry the level of apoptosis was evaluated.
RESULTS
The uncontrolled undirected cholesteatoma growth shows an immunomodulatory profile with up and down-regulation of various gene networks, especially those involved in TNF downstream and upstream signaling pathways. TNF in cholesteatoma is modulated both inflammatorily and apoptotically and therefore is suitable as a possible therapeutic approach in various models.
CONCLUSIONS
Cholestatoma might be immunomodulatory regulated.
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Affiliation(s)
- Anke Leichtle
- Klinik und Poliklinik für Hals-, Nasen- und Ohrenheilkunde, Universitätsklinikum Schleswig-Holstein Campus Lübeck HNO Klinik, Lubeck, Germany
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- David Leffers
- Klinik und Poliklinik für Hals-, Nasen- und Ohrenheilkunde, Universitätsklinikum Schleswig-Holstein Campus Lübeck HNO Klinik, Lubeck, Germany
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- Markus Georg Daerr
- Klinik und Poliklinik für Hals-, Nasen- und Ohrenheilkunde, Universitätsklinikum Schleswig-Holstein Campus Lübeck HNO Klinik, Lubeck, Germany
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- Clara Draf
- Department of Surgery/ Otolaryngology, University of California San Diego, La Jolla, United States
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- Arwa Kurabi
- Department of Surgery/ Otolaryngology, University of California San Diego, La Jolla, United States
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- Allen F Ryan
- Department of Surgery/ Otolaryngology, University of California San Diego, La Jolla, United States
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- Jan Rupp
- Klinik für Infektiologie und Mikrobiologie, Universitätsklinikum Schleswig-Holstein - Campus Lübeck, Luebeck, Germany
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- Karl-Ludwig Bruchhage
- Klinik und Poliklinik für Hals-, Nasen- und Ohrenheilkunde, Universitätsklinikum Schleswig-Holstein Campus Lübeck HNO Klinik, Lubeck, Germany
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Schürmann M, Oppel F, Shao S, Volland-Thurn V, Kaltschmidt C, Kaltschmidt B, Scholtz LU, Sudhoff H. Chronic inflammation of middle ear cholesteatoma promotes its recurrence via a paracrine mechanism.
Cell Commun Signal 2021;
19:25. [PMID:
33627146 PMCID:
PMC7903614 DOI:
10.1186/s12964-020-00690-y]
[Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 11/23/2020] [Indexed: 12/02/2022] Open
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.
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Video Abstract
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Affiliation(s)
- Matthias Schürmann
- Department of Otolaryngology, Head and Neck Surgery, Medical School OWL Campus Klinikum Bielefeld, Bielefeld University, Teutoburger Str. 50, 33604, Bielefeld, Germany
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- Felix Oppel
- Department of Otolaryngology, Head and Neck Surgery, Medical School OWL Campus Klinikum Bielefeld, Bielefeld University, Teutoburger Str. 50, 33604, Bielefeld, Germany
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- Senyao Shao
- Department of Otolaryngology, Head and Neck Surgery, Medical School OWL Campus Klinikum Bielefeld, Bielefeld University, Teutoburger Str. 50, 33604, Bielefeld, Germany
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- Verena Volland-Thurn
- Department of Otolaryngology, Head and Neck Surgery, Medical School OWL Campus Klinikum Bielefeld, Bielefeld University, Teutoburger Str. 50, 33604, Bielefeld, Germany
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- Barbara Kaltschmidt
- Department of Cell Biology, Bielefeld University , 33619, Bielefeld, Germany
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- Lars-Uwe Scholtz
- Department of Otolaryngology, Head and Neck Surgery, Medical School OWL Campus Klinikum Bielefeld, Bielefeld University, Teutoburger Str. 50, 33604, Bielefeld, Germany
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- Holger Sudhoff
- Department of Otolaryngology, Head and Neck Surgery, Medical School OWL Campus Klinikum Bielefeld, Bielefeld University, Teutoburger Str. 50, 33604, Bielefeld, Germany.
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Extensive qPCR analysis reveals altered gene expression in middle ear mucosa from cholesteatoma patients.
PLoS One 2020;
15:e0239161. [PMID:
32915926 PMCID:
PMC7485814 DOI:
10.1371/journal.pone.0239161]
[Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 08/31/2020] [Indexed: 12/21/2022] Open
Abstract
The middle ear is a small and hard to reach compartment, limiting the amount of tissue that can be extracted and the possibilities for studying the molecular mechanisms behind diseases like cholesteatoma. In this paper 14 reference gene candidates were evaluated in the middle ear mucosa of cholesteatoma patients and two different control tissues. ACTB and GAPDH were shown to be the optimal genes for the normalisation of target gene expression when investigating middle ear mucosa in multiplex qPCR analysis. Validation of reference genes using c-MYC expression confirmed the suitability of ACTB and GAPDH as reference genes and showed an upregulation of c-MYC in middle ear mucosa during cholesteatoma. The occurrence of participants of the innate immunity, TLR2 and TLR4, were analysed in order to compare healthy middle ear mucosa to cholesteatoma. Analysis of TLR2 and TLR4 showed variable results depending on control tissue used, highlighting the importance of selecting relevant control tissue when investigating causes for disease. It is our belief that a consensus regarding reference genes and control tissue will contribute to the comparability and reproducibility of studies within the field.
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8
Role of Macrophage Migration Inhibitory Factor in NLRP3 Inflammasome Expression in Otitis Media.
Otol Neurotol 2020;
41:364-370. [DOI:
10.1097/mao.0000000000002537]
[Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Kariya S, Okano M, Zhao P, Maeda Y, Kataoka Y, Higaki T, Noda Y, Makihara S, Nishizaki K. NLRP3 inflammasome expression in lipopolysaccharide-induced otitis media.
Acta Otolaryngol 2018;
138:1061-1065. [PMID:
30676848 DOI:
10.1080/00016489.2018.1515499]
[Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND
The nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome is a critical molecule mediating interleukin-1β (IL-1β) responses. However, the role of the NLRP3 inflammasome in otitis media has not been fully examined.
AIMS/OBJECTIVES
The purpose of this study is to assess the expression of NLRP3, ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain and a pyrin domain), and caspase-1 in lipopolysaccharide-induced otitis media.
MATERIALS AND METHODS
BALB/c mice received a transtympanic injection of either lipopolysaccharide or phosphate-buffered saline. The mice were sacrificed 24 h after injection. Concentrations of IL-1β, NLRP3, ASC, and caspase-1 in the middle ear effusions were measured by enzyme-linked immunosorbent assay. Temporal bones were processed for histologic examination and immunohistochemistry.
RESULTS
The transtympanic injection of lipopolysaccharide significantly upregulated levels of IL-1β, NLRP3, ASC, and caspase-1 in the middle ear as compared with the control mice. The proteins of NLRP3, ASC, and caspase-1 were observed in infiltrating inflammatory cells induced by lipopolysaccharide in the middle ear cavity.
CONCLUSIONS AND SIGNIFICANCE
Lipopolysaccharide induces NLRP3 inflammasome components in the middle ear. The NLRP3 inflammasome may play an important role in the pathogenesis of otitis media. Modulation of inflammasome-mediated inflammation may be a novel therapeutic strategy for otitis media.
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Affiliation(s)
- Shin Kariya
- Department of Otolaryngology-Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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- Mitsuhiro Okano
- Department of Otolaryngology, International University of Health and Welfare School of Medicine, Narita, Japan
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- Pengfei Zhao
- Department of Otolaryngology-Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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- Yukihide Maeda
- Department of Otolaryngology-Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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- Yuko Kataoka
- Department of Otolaryngology-Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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- Takaya Higaki
- Department of Otolaryngology-Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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- Yohei Noda
- Department of Otolaryngology-Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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- Seiichiro Makihara
- Department of Otolaryngology Head and Neck Surgery, Kagawa Rosai Hospital, Marugame, Japan
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- Kazunori Nishizaki
- Department of Otolaryngology-Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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Kim SH, Han SH, Byun JY, Park MS, Kim YI, Yeo SG. Expression of C-type lectin receptor mRNA in chronic otitis media with cholesteatoma.
Acta Otolaryngol 2017;
137:581-587. [PMID:
28440726 DOI:
10.1080/00016489.2016.1269196]
[Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
CONCLUSIONS
The levels of expression of various C-type lectin receptors (CLRs) messenger ribo nucleic acids (mRNAs) were significantly higher in cholesteatomas than in normal skin, suggesting that these CLRs may be involved in the pathogenesis of cholesteatoma.
OBJECTIVES
Altered expression of pattern recognition receptors may be associated with immune responses in patients with cholesteatoma. This study assessed the levels of expression of CLR mRNAs in normal skin and in cholesteatoma.
METHODS
Cholesteatoma specimens were obtained from 38 patients with acquired cholesteatoma. The levels of expression of various CLR mRNAs were assessed quantitatively using real-time RT-PCR (Reverse transcription polymerase chain reaction) and correlated with age, sex, the presence of bacteria, hearing level, frequency of surgery, and degree of ossicle destruction.
RESULTS
The levels of CD206 (cluster of differentiation 206), DEC-205 (Dendritic and epithelial cell-205), MGL (monoacylglycerol lipase), CLEC5A (C-type lectin domain family 5 member A), Dectin-2 (dendrite cell-associated C-type lectin-2), BDCA2 (Blood dendritic cell antigen 2), Mincle, DCIR (dendritic cell immunoreceptor), Dectin-1, MICL (Myeloid inhibitory C type-like lectin), and CLEC12B (C-type lectin domain family 12, member B) mRNAs were significantly higher in cholesteatoma than in control skin samples (p < 0.05). The levels of CLEC5A (C-type lectin domain family 5 member) and Dectin-1 mRNAs were significantly higher in cholesteatomas with ≥2 than ≤1 destroyed ossicles (p < 0.05), and the levels of MGL, Mincle, Dectin-1, and CLEC12B mRNAs were significantly higher in recurrent than initial cholesteatoma specimens (p < 0.05). The level of CLEC5A mRNAs was significantly higher in patients with severe than mild-to-moderate hearing loss (p < 0.05).
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Affiliation(s)
- Sang Hoon Kim
- Department of Otorhinolaryngology-Head and Neck Surgery, Graduate School, Kyung Hee University, Seoul, Korea
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- Seung-Ho Han
- Department of Physiology & Biophysics, School of Medicine, Eulji University, Daejeon, Korea
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- Jae Yong Byun
- Department of Otorhinolaryngology-Head and Neck Surgery, Graduate School, Kyung Hee University, Seoul, Korea
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- Moon Suh Park
- Department of Otorhinolaryngology-Head and Neck Surgery, Graduate School, Kyung Hee University, Seoul, Korea
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- Young Il Kim
- Medical Science Research Institute, Kyung Hee University Medical Center, Seoul, Korea
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- Seung Geun Yeo
- Department of Otorhinolaryngology-Head and Neck Surgery, Graduate School, Kyung Hee University, Seoul, Korea
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Jiang H, Si Y, Li Z, Huang X, Chen S, Zheng Y, Xu G, Chen X, Chen Y, Liu Y, Xiong H, Huang Q, Liang M, Zhang Z. TREM-2 promotes acquired cholesteatoma-induced bone destruction by modulating TLR4 signaling pathway and osteoclasts activation.
Sci Rep 2016;
6:38761. [PMID:
27934908 PMCID:
PMC5146948 DOI:
10.1038/srep38761]
[Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Accepted: 11/07/2016] [Indexed: 02/08/2023] Open
Abstract
Triggering receptor expressed on myeloid cells (TREM) has been broadly studied in inflammatory disease. However, the expression and function of TREM-2 remain undiscovered in acquired cholesteatoma. The expression of TREM-2 was significantly higher in human acquired cholesteatoma than in normal skin from the external auditory canal, and its expression level was positively correlated with the severity of bone destruction. Furthermore, TREM-2 was mainly expressed on dendritic cells (DCs). In human acquired cholesteatoma, the expression of proinflammatory cytokines (IL-1β, TNF-α and IL-6) and matrix metalloproteinases (MMP-2, MMP-8 and MMP-9) were up-regulated, and their expression levels were positively correlated with TREM-2 expression. Osteoclasts were activated in human acquired cholesteatoma. In an animal model, TREM-2 was up-regulated in mice with experimentally acquired cholesteatoma. TREM-2 deficiency impaired the maturation of experimentally acquired cholesteatoma and protected against bone destruction induced by experimentally acquired cholesteatoma. Additional data showed that TREM-2 up-regulated IL-1β and IL-6 expression via TLR4 instead of the TLR2 signaling pathway and promoted MMP-2 and MMP-8 secretion and osteoclast activation in experimentally acquired cholesteatoma. Therefore, TREM-2 might enhance acquired cholesteatoma-induced bone destruction by amplifying the inflammatory response via TLR4 signaling pathways and promoting MMP secretion and osteoclast activation.
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Affiliation(s)
- Huaili Jiang
- Department of Otolaryngology Head and Neck Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, China
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- Yu Si
- Department of Otolaryngology Head and Neck Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, China
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- Zhuohao Li
- Department of Otolaryngology Head and Neck Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, China
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- Xi Huang
- Department of Immunology, Institute of Human Virology, Zhongshan School of Medicine and Key Laboratory of Tropical Diseases Control, Ministry of Education Sun Yat-sen University, Guangzhou, China
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- Suijun Chen
- Department of Otolaryngology Head and Neck Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, China
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- Yiqing Zheng
- Department of Otolaryngology Head and Neck Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, China
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- Guo Xu
- Department of Otolaryngology Head and Neck Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, China
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- Ximing Chen
- Department of Otolaryngology Head and Neck Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, China
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- Yubin Chen
- Department of Otolaryngology Head and Neck Surgery, The third affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
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- Yi Liu
- Department of Otolaryngology Head and Neck Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, China
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- Hao Xiong
- Department of Otolaryngology Head and Neck Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, China
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- Qiuhong Huang
- Department of Otolaryngology Head and Neck Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, China
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- Maojin Liang
- Department of Otolaryngology Head and Neck Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, China
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- Zhigang Zhang
- Department of Otolaryngology Head and Neck Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, China
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12
Kariya S, Okano M, Zhao P, Kataoka Y, Yoshinobu J, Maeda Y, Ishihara H, Higaki T, Nishizaki K. Activation of NLRP3 inflammasome in human middle ear cholesteatoma and chronic otitis media.
Acta Otolaryngol 2015;
136:136-40. [PMID:
26457439 DOI:
10.3109/00016489.2015.1093171]
[Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
CONCLUSIONS
The nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome plays an important role in the pathogenesis of middle ear diseases. Modulation of inflammasome-mediated inflammation may be a novel therapeutic strategy for cholesteatoma and chronic otitis media.
OBJECTIVE
NLRP3 inflammasome is a critical molecule mediating interleukin (IL)-1β responses. However, the expression of NLRP3 in the pathogenesis of cholesteatoma and chronic otitis media has not been fully examined. This study sought to assess the expression of NLRP3, ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain and a pyrin domain), and caspase-1 in middle ear tissues in patients with cholesteatoma or chronic otitis media.
METHODS
Middle ear tissue samples were obtained from patients with cholesteatoma or chronic otitis media. Control middle ear samples were collected during cochlear implant surgery of patients without middle ear inflammation. The expression of NLRP3, ASC, and caspase-1 were examined by reverse transcription polymerase chain reaction (RT-PCR) assay and immunohistochemical study.
RESULTS
The levels of mRNA of NLRP3, ASC, and caspase-1 were significantly elevated in cholesteatoma and chronic otitis media as compared with that of normal controls. The proteins of NLRP3, ASC, and caspase-1 were observed in infiltrating inflammatory cells in cholesteatoma and chronic otitis media.
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Affiliation(s)
- Shin Kariya
- a Department of Otolaryngology-Head and Neck Surgery , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan
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- Mitsuhiro Okano
- a Department of Otolaryngology-Head and Neck Surgery , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan
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- Pengfei Zhao
- a Department of Otolaryngology-Head and Neck Surgery , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan
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- Yuko Kataoka
- a Department of Otolaryngology-Head and Neck Surgery , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan
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- Junko Yoshinobu
- a Department of Otolaryngology-Head and Neck Surgery , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan
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- Yukihide Maeda
- a Department of Otolaryngology-Head and Neck Surgery , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan
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- Hisashi Ishihara
- a Department of Otolaryngology-Head and Neck Surgery , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan
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- Takaya Higaki
- a Department of Otolaryngology-Head and Neck Surgery , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan
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- Kazunori Nishizaki
- a Department of Otolaryngology-Head and Neck Surgery , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan
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13
NOD-Like Receptor Signaling in Cholesteatoma.
BIOMED RESEARCH INTERNATIONAL 2015;
2015:408169. [PMID:
25922834 PMCID:
PMC4398947 DOI:
10.1155/2015/408169]
[Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/02/2015] [Accepted: 03/14/2015] [Indexed: 11/18/2022]
Abstract
Background. Cholesteatoma is a destructive process of the middle ear resulting in erosion of the surrounding bony structures with consequent hearing loss, vestibular dysfunction, facial paralysis, or intracranial complications. The etiopathogenesis of cholesteatoma is controversial but is associated with recurrent ear infections. The role of intracellular innate immune receptors, the NOD-like receptors, and their associated signaling networks was investigated in cholesteatoma, since mutations in NOD-like receptor-related genes have been implicated in other chronic inflammatory disorders. Results. The expression of NOD2 mRNA and protein was significantly induced in cholesteatoma compared to the external auditory canal skin, mainly located in the epithelial layer of cholesteatoma. Microarray analysis showed significant upregulation for NOD2, not for NOD1, TLR2, or TLR4 in cholesteatoma. Moreover, regulation of genes in an interaction network of the NOD-adaptor molecule RIPK2 was detected. In addition to NOD2, NLRC4, and PYCARD, the downstream molecules IRAK1 and antiapoptotic regulator CFLAR showed significant upregulation, whereas SMAD3, a proapoptotic inducer, was significantly downregulated. Finally, altered regulation of inflammatory target genes of NOD signaling was detected. Conclusions. These results indicate that the interaction of innate immune signaling mediated by NLRs and their downstream target molecules is involved in the etiopathogenesis and growth of cholesteatoma.
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14
Kim MG, Park DC, Oh IH, Kim YI, Choi SA, Jung SY, Kang HM, Yeo SG. Increased expression of Dec-205, Bcl-10, Tim-3, and Trem-1 mRNA in chronic otitis media with cholesteatoma.
Acta Otolaryngol 2014;
134:475-80. [PMID:
24702227 DOI:
10.3109/00016489.2013.878474]
[Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
CONCLUSION
The increased expression of Dec-205, Bcl-10, Tim-3, and Trem-1 mRNAs indicates that these pattern recognition receptors are involved in the pathogenesis of cholesteatoma.
OBJECTIVE
Changes in expression of pattern recognition receptors may be associated with immune responses in patients with cholesteatoma. We therefore assessed the levels of expression of Dec-205, Bcl-10, Tim-3, and Trem-1 mRNAs associated with innate immune responses in patients with cholesteatoma.
METHODS
Cholesteatoma specimens were collected from 23 patients diagnosed with acquired cholesteatoma from August 2010 to July 2012. The posterior auricular skin of each patient was used as control. The levels of expression of Dec-205, Bcl-10, Tim-3, and Trem-1 mRNA were assessed quantitatively using real-time RT-PCR and correlated with sex, hearing level, the presence of bacteria, and the need for repeat surgery.
RESULTS
The levels of expression of Dec-205, Bcl-10, Tim-3, and Trem-1 mRNAs were significantly higher in cholesteatoma than in control skin samples (p < 0.05 each). However, mRNA abundance was not associated with patient sex, hearing level, presence of bacteria or history of reoperation (p > 0.05 each).
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Affiliation(s)
- Myung Gu Kim
- Department of Otorhinolaryngology Head and Neck Surgery, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine , Changwon
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