Myocardial Accumulations of Reg3A, Reg3γ and Oncostatin M Are Associated with the Formation of Granulomata in Patients with Cardiac Sarcoidosis
Cardiac sarcoidosis (CS) is a poorly understood disease and is characterized by the focal accumulation of immune cells, thus leading to the formation of granulomata (GL). To identify the developmental principles of fatal GL, fluorescence microscopy and Western blot analysis of CS and control patient...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-04-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/8/4148 |
| _version_ | 1797537365835644928 |
|---|---|
| author | Praveen Gajawada Ayse Cetinkaya Susanne von Gerlach Natalia Kubin Heiko Burger Michael Näbauer Carola Grinninger Andreas Rolf Markus Schönburg Yeong-Hoon Choi Thomas Kubin Manfred Richter |
| author_facet | Praveen Gajawada Ayse Cetinkaya Susanne von Gerlach Natalia Kubin Heiko Burger Michael Näbauer Carola Grinninger Andreas Rolf Markus Schönburg Yeong-Hoon Choi Thomas Kubin Manfred Richter |
| author_sort | Praveen Gajawada |
| collection | DOAJ |
| description | Cardiac sarcoidosis (CS) is a poorly understood disease and is characterized by the focal accumulation of immune cells, thus leading to the formation of granulomata (GL). To identify the developmental principles of fatal GL, fluorescence microscopy and Western blot analysis of CS and control patients is presented here. CS is visualized macroscopically by positron emission tomography (PET)/ computed tomography (CT). A battery of antibodies is used to determine structural, cell cycle and inflammatory markers. GL consist of CD68<sup>+</sup>, CD163<sup>+</sup> and CD206<sup>+</sup> macrophages surrounded by T-cells within fibrotic areas. Cell cycle markers such as phospho-histone H3, phospho-Aurora and Ki67 were moderately present; however, the phosphorylated ERM (ezrin, radixin and moesin) and Erk1/2 proteins, strong expression of the myosin motor protein and the macrophage transcription factor PU.1 indicate highly active GL. Mild apoptosis is consistent with PI3 kinase and Akt activation. Massive amounts of the IL-1R antagonist reflect a mild activation of stress and inflammatory pathways in GL. High levels of oncostatin M and the Reg3A and Reg3γ chemokines are in accordance with macrophage accumulation in areas of remodeling cardiomyocytes. We conclude that the formation of GL occurs mainly through chemoattraction and less by proliferation of macrophages. Furthermore, activation of the oncostatin/Reg3 axis might help at first to wall-off substances but might initiate the chronic development of heart failure. |
| first_indexed | 2024-03-10T12:14:07Z |
| format | Article |
| id | doaj.art-16de534d08fa4448ba55981d9f151559 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T12:14:07Z |
| publishDate | 2021-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-16de534d08fa4448ba55981d9f1515592023-11-21T15:55:52ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-04-01228414810.3390/ijms22084148Myocardial Accumulations of Reg3A, Reg3γ and Oncostatin M Are Associated with the Formation of Granulomata in Patients with Cardiac SarcoidosisPraveen Gajawada0Ayse Cetinkaya1Susanne von Gerlach2Natalia Kubin3Heiko Burger4Michael Näbauer5Carola Grinninger6Andreas Rolf7Markus Schönburg8Yeong-Hoon Choi9Thomas Kubin10Manfred Richter11Department of Cardiac Surgery, Kerckhoff Heart Center, Benekestr. 2-8, 61231 Bad Nauheim, GermanyDepartment of Cardiac Surgery, Kerckhoff Heart Center, Benekestr. 2-8, 61231 Bad Nauheim, GermanyUniversitätsklinikum Giessen und Marburg GmbH, Standort Marburg, Baldingerstr., 35033 Marburg, GermanyDepartment of Cardiac Surgery, Kerckhoff Heart Center, Benekestr. 2-8, 61231 Bad Nauheim, GermanyDepartment of Cardiac Surgery, Kerckhoff Heart Center, Benekestr. 2-8, 61231 Bad Nauheim, GermanyMedizinische Klinik und Poliklinik I, Klinikum der Universität München, Marchioninistr. 15, 81377 Munich, GermanyMedizinische Klinik und Poliklinik I, Klinikum der Universität München, Marchioninistr. 15, 81377 Munich, GermanyCampus Kerckhoff, Justus-Liebig-University Giessen, 61231 Bad Nauheim, GermanyDepartment of Cardiac Surgery, Kerckhoff Heart Center, Benekestr. 2-8, 61231 Bad Nauheim, GermanyDepartment of Cardiac Surgery, Kerckhoff Heart Center, Benekestr. 2-8, 61231 Bad Nauheim, GermanyDepartment of Cardiac Surgery, Kerckhoff Heart Center, Benekestr. 2-8, 61231 Bad Nauheim, GermanyDepartment of Cardiac Surgery, Kerckhoff Heart Center, Benekestr. 2-8, 61231 Bad Nauheim, GermanyCardiac sarcoidosis (CS) is a poorly understood disease and is characterized by the focal accumulation of immune cells, thus leading to the formation of granulomata (GL). To identify the developmental principles of fatal GL, fluorescence microscopy and Western blot analysis of CS and control patients is presented here. CS is visualized macroscopically by positron emission tomography (PET)/ computed tomography (CT). A battery of antibodies is used to determine structural, cell cycle and inflammatory markers. GL consist of CD68<sup>+</sup>, CD163<sup>+</sup> and CD206<sup>+</sup> macrophages surrounded by T-cells within fibrotic areas. Cell cycle markers such as phospho-histone H3, phospho-Aurora and Ki67 were moderately present; however, the phosphorylated ERM (ezrin, radixin and moesin) and Erk1/2 proteins, strong expression of the myosin motor protein and the macrophage transcription factor PU.1 indicate highly active GL. Mild apoptosis is consistent with PI3 kinase and Akt activation. Massive amounts of the IL-1R antagonist reflect a mild activation of stress and inflammatory pathways in GL. High levels of oncostatin M and the Reg3A and Reg3γ chemokines are in accordance with macrophage accumulation in areas of remodeling cardiomyocytes. We conclude that the formation of GL occurs mainly through chemoattraction and less by proliferation of macrophages. Furthermore, activation of the oncostatin/Reg3 axis might help at first to wall-off substances but might initiate the chronic development of heart failure.https://www.mdpi.com/1422-0067/22/8/4148chemokinechemoattractionmacrophageinflammationinterleukin-1 receptor antagonistcell signaling |
| spellingShingle | Praveen Gajawada Ayse Cetinkaya Susanne von Gerlach Natalia Kubin Heiko Burger Michael Näbauer Carola Grinninger Andreas Rolf Markus Schönburg Yeong-Hoon Choi Thomas Kubin Manfred Richter Myocardial Accumulations of Reg3A, Reg3γ and Oncostatin M Are Associated with the Formation of Granulomata in Patients with Cardiac Sarcoidosis International Journal of Molecular Sciences chemokine chemoattraction macrophage inflammation interleukin-1 receptor antagonist cell signaling |
| title | Myocardial Accumulations of Reg3A, Reg3γ and Oncostatin M Are Associated with the Formation of Granulomata in Patients with Cardiac Sarcoidosis |
| title_full | Myocardial Accumulations of Reg3A, Reg3γ and Oncostatin M Are Associated with the Formation of Granulomata in Patients with Cardiac Sarcoidosis |
| title_fullStr | Myocardial Accumulations of Reg3A, Reg3γ and Oncostatin M Are Associated with the Formation of Granulomata in Patients with Cardiac Sarcoidosis |
| title_full_unstemmed | Myocardial Accumulations of Reg3A, Reg3γ and Oncostatin M Are Associated with the Formation of Granulomata in Patients with Cardiac Sarcoidosis |
| title_short | Myocardial Accumulations of Reg3A, Reg3γ and Oncostatin M Are Associated with the Formation of Granulomata in Patients with Cardiac Sarcoidosis |
| title_sort | myocardial accumulations of reg3a reg3γ and oncostatin m are associated with the formation of granulomata in patients with cardiac sarcoidosis |
| topic | chemokine chemoattraction macrophage inflammation interleukin-1 receptor antagonist cell signaling |
| url | https://www.mdpi.com/1422-0067/22/8/4148 |
| work_keys_str_mv | AT praveengajawada myocardialaccumulationsofreg3areg3gandoncostatinmareassociatedwiththeformationofgranulomatainpatientswithcardiacsarcoidosis AT aysecetinkaya myocardialaccumulationsofreg3areg3gandoncostatinmareassociatedwiththeformationofgranulomatainpatientswithcardiacsarcoidosis AT susannevongerlach myocardialaccumulationsofreg3areg3gandoncostatinmareassociatedwiththeformationofgranulomatainpatientswithcardiacsarcoidosis AT nataliakubin myocardialaccumulationsofreg3areg3gandoncostatinmareassociatedwiththeformationofgranulomatainpatientswithcardiacsarcoidosis AT heikoburger myocardialaccumulationsofreg3areg3gandoncostatinmareassociatedwiththeformationofgranulomatainpatientswithcardiacsarcoidosis AT michaelnabauer myocardialaccumulationsofreg3areg3gandoncostatinmareassociatedwiththeformationofgranulomatainpatientswithcardiacsarcoidosis AT carolagrinninger myocardialaccumulationsofreg3areg3gandoncostatinmareassociatedwiththeformationofgranulomatainpatientswithcardiacsarcoidosis AT andreasrolf myocardialaccumulationsofreg3areg3gandoncostatinmareassociatedwiththeformationofgranulomatainpatientswithcardiacsarcoidosis AT markusschonburg myocardialaccumulationsofreg3areg3gandoncostatinmareassociatedwiththeformationofgranulomatainpatientswithcardiacsarcoidosis AT yeonghoonchoi myocardialaccumulationsofreg3areg3gandoncostatinmareassociatedwiththeformationofgranulomatainpatientswithcardiacsarcoidosis AT thomaskubin myocardialaccumulationsofreg3areg3gandoncostatinmareassociatedwiththeformationofgranulomatainpatientswithcardiacsarcoidosis AT manfredrichter myocardialaccumulationsofreg3areg3gandoncostatinmareassociatedwiththeformationofgranulomatainpatientswithcardiacsarcoidosis |