miR-223 and Chromogranin A Affect Inflammatory Immune Cell Activation in Liver Metastasis of Neuroendocrine Neoplasms
Neuroendocrine neoplasms (NENs) are a diverse group originating from endocrine cells/their precursors in pancreas, small intestine, or lung. The key serum marker is chromogranin A (CgA). While commonly elevated in patients with NEN, its prognostic value is still under discussion. Secretion/posttrans...
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2025-01-01
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| author | Lukas Geisler Katharina Detjen Teresa Hellberg Marlene Kohlhepp Carsten Grötzinger Jana Knorr Ines Eichhorn Raphael Mohr Theresa Holtmann Bertram Wiedenmann Frank Tacke Christoph Roderburg Alexander Wree |
| author_facet | Lukas Geisler Katharina Detjen Teresa Hellberg Marlene Kohlhepp Carsten Grötzinger Jana Knorr Ines Eichhorn Raphael Mohr Theresa Holtmann Bertram Wiedenmann Frank Tacke Christoph Roderburg Alexander Wree |
| author_sort | Lukas Geisler |
| collection | DOAJ |
| description | Neuroendocrine neoplasms (NENs) are a diverse group originating from endocrine cells/their precursors in pancreas, small intestine, or lung. The key serum marker is chromogranin A (CgA). While commonly elevated in patients with NEN, its prognostic value is still under discussion. Secretion/posttranslational proteolytic cleavage of CgA results in multiple bioactive fragments, which are essential regulators of the cardiovascular and immune system. miR-223, regulator of Nrlp3 inflammasome and neutrophil activation, was recently found to have decreased in patients with NEN. We performed flow cytometry of circulating neutrophils in a patient cohort (n = 10) with NEN, microdissection and histology of tumor tissue. Subsequently, in vitro transfections using the well-established human pancreatic NEN cell line (BON), and co-culture experiments with primary macrophages and neutrophils were performed. Serum miR-223 in patients correlated with the expression of the neutrophil activation marker CD15 in circulating cells. Neutrophilic CD62L/CD63 showed good discrimination compared to healthy controls. Immune cell-derived miR-155, miR-193 and miR-223 colocalize with neutrophil in the extra-tumoral tissue alongside Nlrp3-associated caspase-1 activation. miR-223 knockdown in BON decreased the CgA intracellularly, increased in cellular granularity and caspase-1 activation. Plasmin inhibitor a2-aP reverted those effects. Western Blot showed fragmented CgA following miR-223 knockdown, which altered the inflammatory potential of neutrophils. Our data hence provide initial insights into an immunoregulatory mechanism via miR-223 and CgA in NEN cells, as regulation of miR-223 in NEN may affect tumor-associated inflammation. |
| format | Article |
| id | doaj-art-5e9186656998498baddd62348fc176b3 |
| institution | Kabale University |
| issn | 2073-4409 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj-art-5e9186656998498baddd62348fc176b32025-01-24T13:26:42ZengMDPI AGCells2073-44092025-01-0114211110.3390/cells14020111miR-223 and Chromogranin A Affect Inflammatory Immune Cell Activation in Liver Metastasis of Neuroendocrine NeoplasmsLukas Geisler0Katharina Detjen1Teresa Hellberg2Marlene Kohlhepp3Carsten Grötzinger4Jana Knorr5Ines Eichhorn6Raphael Mohr7Theresa Holtmann8Bertram Wiedenmann9Frank Tacke10Christoph Roderburg11Alexander Wree12Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, 13353 Berlin, GermanyDepartment of Hepatology and Gastroenterology, Charité University Medicine Berlin, 13353 Berlin, GermanyDepartment of Hepatology and Gastroenterology, Charité University Medicine Berlin, 13353 Berlin, GermanyDepartment of Hepatology and Gastroenterology, Charité University Medicine Berlin, 13353 Berlin, GermanyDepartment of Hepatology and Gastroenterology, Charité University Medicine Berlin, 13353 Berlin, GermanyDepartment of Hepatology and Gastroenterology, Charité University Medicine Berlin, 13353 Berlin, GermanyDepartment of Hepatology and Gastroenterology, Charité University Medicine Berlin, 13353 Berlin, GermanyDepartment of Hepatology and Gastroenterology, Charité University Medicine Berlin, 13353 Berlin, GermanyDepartment of Hepatology and Gastroenterology, Charité University Medicine Berlin, 13353 Berlin, GermanyDepartment of Hepatology and Gastroenterology, Charité University Medicine Berlin, 13353 Berlin, GermanyDepartment of Hepatology and Gastroenterology, Charité University Medicine Berlin, 13353 Berlin, GermanyDepartment of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, 40225 Düsseldorf, GermanyDepartment of Hepatology and Gastroenterology, Charité University Medicine Berlin, 13353 Berlin, GermanyNeuroendocrine neoplasms (NENs) are a diverse group originating from endocrine cells/their precursors in pancreas, small intestine, or lung. The key serum marker is chromogranin A (CgA). While commonly elevated in patients with NEN, its prognostic value is still under discussion. Secretion/posttranslational proteolytic cleavage of CgA results in multiple bioactive fragments, which are essential regulators of the cardiovascular and immune system. miR-223, regulator of Nrlp3 inflammasome and neutrophil activation, was recently found to have decreased in patients with NEN. We performed flow cytometry of circulating neutrophils in a patient cohort (n = 10) with NEN, microdissection and histology of tumor tissue. Subsequently, in vitro transfections using the well-established human pancreatic NEN cell line (BON), and co-culture experiments with primary macrophages and neutrophils were performed. Serum miR-223 in patients correlated with the expression of the neutrophil activation marker CD15 in circulating cells. Neutrophilic CD62L/CD63 showed good discrimination compared to healthy controls. Immune cell-derived miR-155, miR-193 and miR-223 colocalize with neutrophil in the extra-tumoral tissue alongside Nlrp3-associated caspase-1 activation. miR-223 knockdown in BON decreased the CgA intracellularly, increased in cellular granularity and caspase-1 activation. Plasmin inhibitor a2-aP reverted those effects. Western Blot showed fragmented CgA following miR-223 knockdown, which altered the inflammatory potential of neutrophils. Our data hence provide initial insights into an immunoregulatory mechanism via miR-223 and CgA in NEN cells, as regulation of miR-223 in NEN may affect tumor-associated inflammation.https://www.mdpi.com/2073-4409/14/2/111neuroendocrine neoplasmmiR-223Nlrp3neutrophil |
| spellingShingle | Lukas Geisler Katharina Detjen Teresa Hellberg Marlene Kohlhepp Carsten Grötzinger Jana Knorr Ines Eichhorn Raphael Mohr Theresa Holtmann Bertram Wiedenmann Frank Tacke Christoph Roderburg Alexander Wree miR-223 and Chromogranin A Affect Inflammatory Immune Cell Activation in Liver Metastasis of Neuroendocrine Neoplasms Cells neuroendocrine neoplasm miR-223 Nlrp3 neutrophil |
| title | miR-223 and Chromogranin A Affect Inflammatory Immune Cell Activation in Liver Metastasis of Neuroendocrine Neoplasms |
| title_full | miR-223 and Chromogranin A Affect Inflammatory Immune Cell Activation in Liver Metastasis of Neuroendocrine Neoplasms |
| title_fullStr | miR-223 and Chromogranin A Affect Inflammatory Immune Cell Activation in Liver Metastasis of Neuroendocrine Neoplasms |
| title_full_unstemmed | miR-223 and Chromogranin A Affect Inflammatory Immune Cell Activation in Liver Metastasis of Neuroendocrine Neoplasms |
| title_short | miR-223 and Chromogranin A Affect Inflammatory Immune Cell Activation in Liver Metastasis of Neuroendocrine Neoplasms |
| title_sort | mir 223 and chromogranin a affect inflammatory immune cell activation in liver metastasis of neuroendocrine neoplasms |
| topic | neuroendocrine neoplasm miR-223 Nlrp3 neutrophil |
| url | https://www.mdpi.com/2073-4409/14/2/111 |
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