Anti-inflammatory and immunomodulating effects of rilpivirine: Relevance for the therapeutics of chronic liver disease
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease (CLD) worldwide and inflammation is key to its progression/resolution. As we have previously described that rilpivirine (RPV) is hepatoprotective in murine models of CLD, here we determine the molecular mecha...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-11-01
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| Series: | Biomedicine & Pharmacotherapy |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332223013355 |
| _version_ | 1797660559946022912 |
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| author | Angela B. Moragrega Aleksandra Gruevska Isabel Fuster-Martínez Ana M. Benedicto Joan Tosca Cristina Montón Victor M. Victor Juan V. Esplugues Ana Blas-García Nadezda Apostolova |
| author_facet | Angela B. Moragrega Aleksandra Gruevska Isabel Fuster-Martínez Ana M. Benedicto Joan Tosca Cristina Montón Victor M. Victor Juan V. Esplugues Ana Blas-García Nadezda Apostolova |
| author_sort | Angela B. Moragrega |
| collection | DOAJ |
| description | Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease (CLD) worldwide and inflammation is key to its progression/resolution. As we have previously described that rilpivirine (RPV) is hepatoprotective in murine models of CLD, here we determine the molecular mechanisms involved, focusing on its anti-inflammatory and immunomodulating properties. They were evaluated in vitro (human hepatic cell lines of the major hepatic cell types), in vivo (liver samples from a murine nutritional model of NAFLD) and ex vivo (peripheral blood mononuclear cells -PBMC- from patients with CLD). Transcriptomic analysis of liver samples from NAFLD mice showed RPV down-regulated biological processes associated with the inflammatory response (NF-κB/IκB signaling and mitogen-activated protein kinase -MAPK- activity) and leukocyte chemotaxis and migration. We observed a decrease in Adgre1 and Ccr2 expression and in the number of CCR2 + cells in the periportal areas of RPV-treated NAFLD mice. This RPV-induced effect on the CCL2/CCR2 axis was confirmed in vitro. A similar result was also obtained with CXCL10/IP10, one of the main chemokines in the liver. RPV also diminished activation of MAP kinases p38 and JNK. In addition, RPV inhibited the NLRP3 inflammasome pathway in vitro, decreasing NLRP3 protein expression, caspase-1 activation and IL-1β gene expression. RPV was also proven anti-inflammatory in PBMC from patients with CLD treated ex vivo. In conclusion, beyond its well-described role in antiretroviral therapy, RPV manifests anti-inflammatory and immunoregulatory effects, a finding that could be of great relevance for the search of novel targets or repositioning strategies for CLD. |
| first_indexed | 2024-03-11T18:31:40Z |
| format | Article |
| id | doaj.art-2a96dfa401664d44b04a36bbadd0858b |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-03-11T18:31:40Z |
| publishDate | 2023-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-2a96dfa401664d44b04a36bbadd0858b2023-10-13T11:03:00ZengElsevierBiomedicine & Pharmacotherapy0753-33222023-11-01167115537Anti-inflammatory and immunomodulating effects of rilpivirine: Relevance for the therapeutics of chronic liver diseaseAngela B. Moragrega0Aleksandra Gruevska1Isabel Fuster-Martínez2Ana M. Benedicto3Joan Tosca4Cristina Montón5Victor M. Victor6Juan V. Esplugues7Ana Blas-García8Nadezda Apostolova9Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain; FISABIO–Hospital Universitario Dr. Peset, Valencia, SpainDepartamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain; FISABIO–Hospital Universitario Dr. Peset, Valencia, SpainDepartamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain; FISABIO–Hospital Universitario Dr. Peset, Valencia, SpainDepartamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain; FISABIO–Hospital Universitario Dr. Peset, Valencia, SpainDepartmento de Medicina Digestiva, Hospital Clínico Universitario de Valencia, Valencia, SpainDepartmento de Medicina Digestiva, Hospital Clínico Universitario de Valencia, Valencia, SpainFISABIO–Hospital Universitario Dr. Peset, Valencia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain; Fundación para la Investigación del Hospital Clínico de la Comunidad Valenciana (INCLIVA), Valencia, Spain; Departamento de Fisiología, Facultad de Medicina, Universidad de Valencia, Valencia, SpainDepartamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain; FISABIO–Hospital Universitario Dr. Peset, Valencia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), SpainFISABIO–Hospital Universitario Dr. Peset, Valencia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain; Departamento de Fisiología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain; Correspondence to: Departamento de Farmacología y Departmento de Fisiología, Universitat de València.Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain; FISABIO–Hospital Universitario Dr. Peset, Valencia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain; Correspondence to: Departamento de Farmacología y Departmento de Fisiología, Universitat de València.Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease (CLD) worldwide and inflammation is key to its progression/resolution. As we have previously described that rilpivirine (RPV) is hepatoprotective in murine models of CLD, here we determine the molecular mechanisms involved, focusing on its anti-inflammatory and immunomodulating properties. They were evaluated in vitro (human hepatic cell lines of the major hepatic cell types), in vivo (liver samples from a murine nutritional model of NAFLD) and ex vivo (peripheral blood mononuclear cells -PBMC- from patients with CLD). Transcriptomic analysis of liver samples from NAFLD mice showed RPV down-regulated biological processes associated with the inflammatory response (NF-κB/IκB signaling and mitogen-activated protein kinase -MAPK- activity) and leukocyte chemotaxis and migration. We observed a decrease in Adgre1 and Ccr2 expression and in the number of CCR2 + cells in the periportal areas of RPV-treated NAFLD mice. This RPV-induced effect on the CCL2/CCR2 axis was confirmed in vitro. A similar result was also obtained with CXCL10/IP10, one of the main chemokines in the liver. RPV also diminished activation of MAP kinases p38 and JNK. In addition, RPV inhibited the NLRP3 inflammasome pathway in vitro, decreasing NLRP3 protein expression, caspase-1 activation and IL-1β gene expression. RPV was also proven anti-inflammatory in PBMC from patients with CLD treated ex vivo. In conclusion, beyond its well-described role in antiretroviral therapy, RPV manifests anti-inflammatory and immunoregulatory effects, a finding that could be of great relevance for the search of novel targets or repositioning strategies for CLD.http://www.sciencedirect.com/science/article/pii/S0753332223013355Liver diseaseInflammationRilpivirineLeukocytesMacrophages |
| spellingShingle | Angela B. Moragrega Aleksandra Gruevska Isabel Fuster-Martínez Ana M. Benedicto Joan Tosca Cristina Montón Victor M. Victor Juan V. Esplugues Ana Blas-García Nadezda Apostolova Anti-inflammatory and immunomodulating effects of rilpivirine: Relevance for the therapeutics of chronic liver disease Biomedicine & Pharmacotherapy Liver disease Inflammation Rilpivirine Leukocytes Macrophages |
| title | Anti-inflammatory and immunomodulating effects of rilpivirine: Relevance for the therapeutics of chronic liver disease |
| title_full | Anti-inflammatory and immunomodulating effects of rilpivirine: Relevance for the therapeutics of chronic liver disease |
| title_fullStr | Anti-inflammatory and immunomodulating effects of rilpivirine: Relevance for the therapeutics of chronic liver disease |
| title_full_unstemmed | Anti-inflammatory and immunomodulating effects of rilpivirine: Relevance for the therapeutics of chronic liver disease |
| title_short | Anti-inflammatory and immunomodulating effects of rilpivirine: Relevance for the therapeutics of chronic liver disease |
| title_sort | anti inflammatory and immunomodulating effects of rilpivirine relevance for the therapeutics of chronic liver disease |
| topic | Liver disease Inflammation Rilpivirine Leukocytes Macrophages |
| url | http://www.sciencedirect.com/science/article/pii/S0753332223013355 |
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