Mechanisms of mesothelial cell response to viral infections: HDAC1-3 inhibition blocks poly(I:C)-induced type I interferon response and modulates the mesenchymal/inflammatory phenotype
Infectious peritonitis is a leading cause of peritoneal functional impairment and a primary factor for therapy discontinuation in peritoneal dialysis (PD) patients. Although bacterial infections are a common cause of peritonitis episodes, emerging evidence suggests a role for viral pathogens. Toll-l...
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| Language: | English |
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Frontiers Media S.A.
2024-02-01
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| Series: | Frontiers in Cellular and Infection Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcimb.2024.1308362/full |
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| author | Flavia Trionfetti Flavia Trionfetti Claudia Montaldo Ivan Caiello Giulio Bontempi Giulio Bontempi Michela Terri Marta Tiberi Vanessa Marchant Vanessa Marchant Alessandro Domenici Paolo Menè Marco Cordani Marco Cordani Clemens Zwergel Giusi Prencipe Marta Ruiz-Ortega Marta Ruiz-Ortega Sergio Valente Antonello Mai Marco Tripodi Marco Tripodi Raffaele Strippoli Raffaele Strippoli |
| author_facet | Flavia Trionfetti Flavia Trionfetti Claudia Montaldo Ivan Caiello Giulio Bontempi Giulio Bontempi Michela Terri Marta Tiberi Vanessa Marchant Vanessa Marchant Alessandro Domenici Paolo Menè Marco Cordani Marco Cordani Clemens Zwergel Giusi Prencipe Marta Ruiz-Ortega Marta Ruiz-Ortega Sergio Valente Antonello Mai Marco Tripodi Marco Tripodi Raffaele Strippoli Raffaele Strippoli |
| author_sort | Flavia Trionfetti |
| collection | DOAJ |
| description | Infectious peritonitis is a leading cause of peritoneal functional impairment and a primary factor for therapy discontinuation in peritoneal dialysis (PD) patients. Although bacterial infections are a common cause of peritonitis episodes, emerging evidence suggests a role for viral pathogens. Toll-like receptors (TLRs) specifically recognize conserved pathogen-associated molecular patterns (PAMPs) from bacteria, viruses, and fungi, thereby orchestrating the ensuing inflammatory/immune responses. Among TLRs, TLR3 recognizes viral dsRNA and triggers antiviral response cascades upon activation. Epigenetic regulation, mediated by histone deacetylase (HDAC), has been demonstrated to control several cellular functions in response to various extracellular stimuli. Employing epigenetic target modulators, such as epidrugs, is a current therapeutic option in several cancers and holds promise in treating viral diseases. This study aims to elucidate the impact of TLR3 stimulation on the plasticity of human mesothelial cells (MCs) in PD patients and to investigate the effects of HDAC1-3 inhibition. Treatment of MCs from PD patients with the TLR3 agonist polyinosinic:polycytidylic acid (Poly(I:C)), led to the acquisition of a bona fide mesothelial-to-mesenchymal transition (MMT) characterized by the upregulation of mesenchymal genes and loss of epithelial-like features. Moreover, Poly(I:C) modulated the expression of several inflammatory cytokines and chemokines. A quantitative proteomic analysis of MCs treated with MS-275, an HDAC1-3 inhibitor, unveiled altered expression of several proteins, including inflammatory cytokines/chemokines and interferon-stimulated genes (ISGs). Treatment with MS-275 facilitated MMT reversal and inhibited the interferon signature, which was associated with reduced STAT1 phosphorylation. However, the modulation of inflammatory cytokine/chemokine production was not univocal, as IL-6 and CXCL8 were augmented while TNF-α and CXCL10 were decreased. Collectively, our findings underline the significance of viral infections in acquiring a mesenchymal-like phenotype by MCs and the potential consequences of virus-associated peritonitis episodes for PD patients. The observed promotion of MMT reversal and interferon response inhibition by an HDAC1-3 inhibitor, albeit without a general impact on inflammatory cytokine production, has translational implications deserving further analysis. |
| first_indexed | 2024-03-07T21:26:24Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2235-2988 |
| language | English |
| last_indexed | 2024-03-07T21:26:24Z |
| publishDate | 2024-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular and Infection Microbiology |
| spelling | doaj.art-f9646b558a1344f187e41e3deecc332e2024-02-27T05:00:29ZengFrontiers Media S.A.Frontiers in Cellular and Infection Microbiology2235-29882024-02-011410.3389/fcimb.2024.13083621308362Mechanisms of mesothelial cell response to viral infections: HDAC1-3 inhibition blocks poly(I:C)-induced type I interferon response and modulates the mesenchymal/inflammatory phenotypeFlavia Trionfetti0Flavia Trionfetti1Claudia Montaldo2Ivan Caiello3Giulio Bontempi4Giulio Bontempi5Michela Terri6Marta Tiberi7Vanessa Marchant8Vanessa Marchant9Alessandro Domenici10Paolo Menè11Marco Cordani12Marco Cordani13Clemens Zwergel14Giusi Prencipe15Marta Ruiz-Ortega16Marta Ruiz-Ortega17Sergio Valente18Antonello Mai19Marco Tripodi20Marco Tripodi21Raffaele Strippoli22Raffaele Strippoli23Department of Molecular Medicine, Sapienza University of Rome, Rome, ItalyGene Expression Laboratory, National Institute for Infectious Diseases, Lazzaro Spallanzani IRCCS, Rome, ItalyGene Expression Laboratory, National Institute for Infectious Diseases, Lazzaro Spallanzani IRCCS, Rome, ItalyDivision of Rheumatology, Ospedale Pediatrico Bambino Gesù IRCCS, Rome, ItalyDepartment of Molecular Medicine, Sapienza University of Rome, Rome, ItalyGene Expression Laboratory, National Institute for Infectious Diseases, Lazzaro Spallanzani IRCCS, Rome, ItalyGene Expression Laboratory, National Institute for Infectious Diseases, Lazzaro Spallanzani IRCCS, Rome, ItalyGene Expression Laboratory, National Institute for Infectious Diseases, Lazzaro Spallanzani IRCCS, Rome, ItalyCellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz-Universidad Autónoma Madrid, Madrid, Spain15 REDINREN/RICORS2040, Madrid, SpainRenal Unit, Department of Clinical and Molecular Medicine, Sant’Andrea University Hospital, Sapienza University of Rome, Rome, ItalyRenal Unit, Department of Clinical and Molecular Medicine, Sant’Andrea University Hospital, Sapienza University of Rome, Rome, ItalyDepartment of Biochemistry and Molecular Biology, Faculty of Biology, Complutense University of Madrid, Madrid, SpainInstituto de Investigaciones Sanitarias San Carlos (IdISSC), Madrid, SpainDepartment of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, ItalyDivision of Rheumatology, Ospedale Pediatrico Bambino Gesù IRCCS, Rome, ItalyCellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz-Universidad Autónoma Madrid, Madrid, Spain15 REDINREN/RICORS2040, Madrid, SpainDepartment of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, ItalyDepartment of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, ItalyDepartment of Molecular Medicine, Sapienza University of Rome, Rome, ItalyGene Expression Laboratory, National Institute for Infectious Diseases, Lazzaro Spallanzani IRCCS, Rome, ItalyDepartment of Molecular Medicine, Sapienza University of Rome, Rome, ItalyGene Expression Laboratory, National Institute for Infectious Diseases, Lazzaro Spallanzani IRCCS, Rome, ItalyInfectious peritonitis is a leading cause of peritoneal functional impairment and a primary factor for therapy discontinuation in peritoneal dialysis (PD) patients. Although bacterial infections are a common cause of peritonitis episodes, emerging evidence suggests a role for viral pathogens. Toll-like receptors (TLRs) specifically recognize conserved pathogen-associated molecular patterns (PAMPs) from bacteria, viruses, and fungi, thereby orchestrating the ensuing inflammatory/immune responses. Among TLRs, TLR3 recognizes viral dsRNA and triggers antiviral response cascades upon activation. Epigenetic regulation, mediated by histone deacetylase (HDAC), has been demonstrated to control several cellular functions in response to various extracellular stimuli. Employing epigenetic target modulators, such as epidrugs, is a current therapeutic option in several cancers and holds promise in treating viral diseases. This study aims to elucidate the impact of TLR3 stimulation on the plasticity of human mesothelial cells (MCs) in PD patients and to investigate the effects of HDAC1-3 inhibition. Treatment of MCs from PD patients with the TLR3 agonist polyinosinic:polycytidylic acid (Poly(I:C)), led to the acquisition of a bona fide mesothelial-to-mesenchymal transition (MMT) characterized by the upregulation of mesenchymal genes and loss of epithelial-like features. Moreover, Poly(I:C) modulated the expression of several inflammatory cytokines and chemokines. A quantitative proteomic analysis of MCs treated with MS-275, an HDAC1-3 inhibitor, unveiled altered expression of several proteins, including inflammatory cytokines/chemokines and interferon-stimulated genes (ISGs). Treatment with MS-275 facilitated MMT reversal and inhibited the interferon signature, which was associated with reduced STAT1 phosphorylation. However, the modulation of inflammatory cytokine/chemokine production was not univocal, as IL-6 and CXCL8 were augmented while TNF-α and CXCL10 were decreased. Collectively, our findings underline the significance of viral infections in acquiring a mesenchymal-like phenotype by MCs and the potential consequences of virus-associated peritonitis episodes for PD patients. The observed promotion of MMT reversal and interferon response inhibition by an HDAC1-3 inhibitor, albeit without a general impact on inflammatory cytokine production, has translational implications deserving further analysis.https://www.frontiersin.org/articles/10.3389/fcimb.2024.1308362/fullmesothelial cellsHDACviral infectionsMMTinterferon responseinflammatory cytokines |
| spellingShingle | Flavia Trionfetti Flavia Trionfetti Claudia Montaldo Ivan Caiello Giulio Bontempi Giulio Bontempi Michela Terri Marta Tiberi Vanessa Marchant Vanessa Marchant Alessandro Domenici Paolo Menè Marco Cordani Marco Cordani Clemens Zwergel Giusi Prencipe Marta Ruiz-Ortega Marta Ruiz-Ortega Sergio Valente Antonello Mai Marco Tripodi Marco Tripodi Raffaele Strippoli Raffaele Strippoli Mechanisms of mesothelial cell response to viral infections: HDAC1-3 inhibition blocks poly(I:C)-induced type I interferon response and modulates the mesenchymal/inflammatory phenotype Frontiers in Cellular and Infection Microbiology mesothelial cells HDAC viral infections MMT interferon response inflammatory cytokines |
| title | Mechanisms of mesothelial cell response to viral infections: HDAC1-3 inhibition blocks poly(I:C)-induced type I interferon response and modulates the mesenchymal/inflammatory phenotype |
| title_full | Mechanisms of mesothelial cell response to viral infections: HDAC1-3 inhibition blocks poly(I:C)-induced type I interferon response and modulates the mesenchymal/inflammatory phenotype |
| title_fullStr | Mechanisms of mesothelial cell response to viral infections: HDAC1-3 inhibition blocks poly(I:C)-induced type I interferon response and modulates the mesenchymal/inflammatory phenotype |
| title_full_unstemmed | Mechanisms of mesothelial cell response to viral infections: HDAC1-3 inhibition blocks poly(I:C)-induced type I interferon response and modulates the mesenchymal/inflammatory phenotype |
| title_short | Mechanisms of mesothelial cell response to viral infections: HDAC1-3 inhibition blocks poly(I:C)-induced type I interferon response and modulates the mesenchymal/inflammatory phenotype |
| title_sort | mechanisms of mesothelial cell response to viral infections hdac1 3 inhibition blocks poly i c induced type i interferon response and modulates the mesenchymal inflammatory phenotype |
| topic | mesothelial cells HDAC viral infections MMT interferon response inflammatory cytokines |
| url | https://www.frontiersin.org/articles/10.3389/fcimb.2024.1308362/full |
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