The S100A4 Transcriptional Inhibitor Niclosamide Reduces Pro-Inflammatory and Migratory Phenotypes of Microglia: Implications for Amyotrophic Lateral Sclerosis
S100A4, belonging to a large multifunctional S100 protein family, is a Ca<sup>2+</sup>-binding protein with a significant role in stimulating the motility of cancer and immune cells, as well as in promoting pro-inflammatory properties in different cell types. In the CNS, there is limited...
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MDPI AG
2019-10-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/8/10/1261 |
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| author | Alessia Serrano Savina Apolloni Simona Rossi Serena Lattante Mario Sabatelli Mina Peric Pavle Andjus Fabrizio Michetti Maria Teresa Carrì Mauro Cozzolino Nadia D’Ambrosi |
| author_facet | Alessia Serrano Savina Apolloni Simona Rossi Serena Lattante Mario Sabatelli Mina Peric Pavle Andjus Fabrizio Michetti Maria Teresa Carrì Mauro Cozzolino Nadia D’Ambrosi |
| author_sort | Alessia Serrano |
| collection | DOAJ |
| description | S100A4, belonging to a large multifunctional S100 protein family, is a Ca<sup>2+</sup>-binding protein with a significant role in stimulating the motility of cancer and immune cells, as well as in promoting pro-inflammatory properties in different cell types. In the CNS, there is limited information concerning S100A4 presence and function. In this study, we analyzed the expression of S100A4 and the effect of the S100A4 transcriptional inhibitor niclosamide in murine activated primary microglia. We found that S100A4 was strongly up-regulated in reactive microglia and that niclosamide prevented NADPH oxidase 2, mTOR (mammalian target of rapamycin), and NF-κB (nuclear factor-kappa B) increase, cytoskeletal rearrangements, migration, and phagocytosis. Furthermore, we found that S100A4 was significantly up-regulated in astrocytes and microglia in the spinal cord of a transgenic rat SOD1-G93A model of amyotrophic lateral sclerosis. Finally, we demonstrated the increased expression of S100A4 also in fibroblasts derived from amyotrophic lateral sclerosis (ALS) patients carrying <i>SOD1</i> pathogenic variants. These results ascribe S100A4 as a marker of microglial reactivity, suggesting the contribution of S100A4-regulated pathways to neuroinflammation, and identify niclosamide as a possible drug in the control and attenuation of reactive phenotypes of microglia, thus opening the way to further investigation for a new application in neurodegenerative conditions. |
| first_indexed | 2024-03-12T08:16:29Z |
| format | Article |
| id | doaj.art-0bf8602007594cdaa08a956c9acebf8d |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-12T08:16:29Z |
| publishDate | 2019-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-0bf8602007594cdaa08a956c9acebf8d2023-09-02T18:48:27ZengMDPI AGCells2073-44092019-10-01810126110.3390/cells8101261cells8101261The S100A4 Transcriptional Inhibitor Niclosamide Reduces Pro-Inflammatory and Migratory Phenotypes of Microglia: Implications for Amyotrophic Lateral SclerosisAlessia Serrano0Savina Apolloni1Simona Rossi2Serena Lattante3Mario Sabatelli4Mina Peric5Pavle Andjus6Fabrizio Michetti7Maria Teresa Carrì8Mauro Cozzolino9Nadia D’Ambrosi10Institute of Anatomy and Cell Biology, Università Cattolica del Sacro Cuore, 00168 Rome, ItalyDepartment of Biology, University of Rome “Tor Vergata”, 00133 Rome, ItalyDepartment of Biology, University of Rome “Tor Vergata”, 00133 Rome, ItalyUnità Operativa Complessa di Genetica Medica, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, ItalyUnità Operativa Complessa di Neurologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, ItalyInstitute of Physiology and Biochemistry “Ivan Djaja”, Faculty of Biology, University of Belgrade, 11000 Belgrade, SerbiaInstitute of Physiology and Biochemistry “Ivan Djaja”, Faculty of Biology, University of Belgrade, 11000 Belgrade, SerbiaInstitute of Anatomy and Cell Biology, Università Cattolica del Sacro Cuore, 00168 Rome, ItalyDepartment of Biology, University of Rome “Tor Vergata”, 00133 Rome, ItalyInstitute of Translational Pharmacology, CNR, 00133 Rome, ItalyDepartment of Biology, University of Rome “Tor Vergata”, 00133 Rome, ItalyS100A4, belonging to a large multifunctional S100 protein family, is a Ca<sup>2+</sup>-binding protein with a significant role in stimulating the motility of cancer and immune cells, as well as in promoting pro-inflammatory properties in different cell types. In the CNS, there is limited information concerning S100A4 presence and function. In this study, we analyzed the expression of S100A4 and the effect of the S100A4 transcriptional inhibitor niclosamide in murine activated primary microglia. We found that S100A4 was strongly up-regulated in reactive microglia and that niclosamide prevented NADPH oxidase 2, mTOR (mammalian target of rapamycin), and NF-κB (nuclear factor-kappa B) increase, cytoskeletal rearrangements, migration, and phagocytosis. Furthermore, we found that S100A4 was significantly up-regulated in astrocytes and microglia in the spinal cord of a transgenic rat SOD1-G93A model of amyotrophic lateral sclerosis. Finally, we demonstrated the increased expression of S100A4 also in fibroblasts derived from amyotrophic lateral sclerosis (ALS) patients carrying <i>SOD1</i> pathogenic variants. These results ascribe S100A4 as a marker of microglial reactivity, suggesting the contribution of S100A4-regulated pathways to neuroinflammation, and identify niclosamide as a possible drug in the control and attenuation of reactive phenotypes of microglia, thus opening the way to further investigation for a new application in neurodegenerative conditions.https://www.mdpi.com/2073-4409/8/10/1261alsastrocytesfibroblastsmicrogliamtorneurodegenerationneuroinflammationnf-κbniclosamides100a4 |
| spellingShingle | Alessia Serrano Savina Apolloni Simona Rossi Serena Lattante Mario Sabatelli Mina Peric Pavle Andjus Fabrizio Michetti Maria Teresa Carrì Mauro Cozzolino Nadia D’Ambrosi The S100A4 Transcriptional Inhibitor Niclosamide Reduces Pro-Inflammatory and Migratory Phenotypes of Microglia: Implications for Amyotrophic Lateral Sclerosis Cells als astrocytes fibroblasts microglia mtor neurodegeneration neuroinflammation nf-κb niclosamide s100a4 |
| title | The S100A4 Transcriptional Inhibitor Niclosamide Reduces Pro-Inflammatory and Migratory Phenotypes of Microglia: Implications for Amyotrophic Lateral Sclerosis |
| title_full | The S100A4 Transcriptional Inhibitor Niclosamide Reduces Pro-Inflammatory and Migratory Phenotypes of Microglia: Implications for Amyotrophic Lateral Sclerosis |
| title_fullStr | The S100A4 Transcriptional Inhibitor Niclosamide Reduces Pro-Inflammatory and Migratory Phenotypes of Microglia: Implications for Amyotrophic Lateral Sclerosis |
| title_full_unstemmed | The S100A4 Transcriptional Inhibitor Niclosamide Reduces Pro-Inflammatory and Migratory Phenotypes of Microglia: Implications for Amyotrophic Lateral Sclerosis |
| title_short | The S100A4 Transcriptional Inhibitor Niclosamide Reduces Pro-Inflammatory and Migratory Phenotypes of Microglia: Implications for Amyotrophic Lateral Sclerosis |
| title_sort | s100a4 transcriptional inhibitor niclosamide reduces pro inflammatory and migratory phenotypes of microglia implications for amyotrophic lateral sclerosis |
| topic | als astrocytes fibroblasts microglia mtor neurodegeneration neuroinflammation nf-κb niclosamide s100a4 |
| url | https://www.mdpi.com/2073-4409/8/10/1261 |
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