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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.
Trionfetti, Flavia; Montaldo, Claudia; Caiello, Ivan; Bontempi, Giulio; Terri, Michela; Tiberi, Marta; Marchant, Vanessa; Domenici, Alessandro; Menè, Paolo; Cordani, Marco; Zwergel, Clemens; Prencipe, Giusi; Ruiz-Ortega, Marta; Valente, Sergio; Mai, Antonello; Tripodi, Marco; Strippoli, Raffaele.
Afiliação
  • Trionfetti F; Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
  • Montaldo C; Gene Expression Laboratory, National Institute for Infectious Diseases, Lazzaro Spallanzani IRCCS, Rome, Italy.
  • Caiello I; Gene Expression Laboratory, National Institute for Infectious Diseases, Lazzaro Spallanzani IRCCS, Rome, Italy.
  • Bontempi G; Division of Rheumatology, Ospedale Pediatrico Bambino Gesù IRCCS, Rome, Italy.
  • Terri M; Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
  • Tiberi M; Gene Expression Laboratory, National Institute for Infectious Diseases, Lazzaro Spallanzani IRCCS, Rome, Italy.
  • Marchant V; Gene Expression Laboratory, National Institute for Infectious Diseases, Lazzaro Spallanzani IRCCS, Rome, Italy.
  • Domenici A; Gene Expression Laboratory, National Institute for Infectious Diseases, Lazzaro Spallanzani IRCCS, Rome, Italy.
  • Menè P; Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz-Universidad Autónoma Madrid, Madrid, Spain.
  • Cordani M; 15 REDINREN/RICORS2040, Madrid, Spain.
  • Zwergel C; Renal Unit, Department of Clinical and Molecular Medicine, Sant'Andrea University Hospital, Sapienza University of Rome, Rome, Italy.
  • Prencipe G; Renal Unit, Department of Clinical and Molecular Medicine, Sant'Andrea University Hospital, Sapienza University of Rome, Rome, Italy.
  • Ruiz-Ortega M; Department of Biochemistry and Molecular Biology, Faculty of Biology, Complutense University of Madrid, Madrid, Spain.
  • Valente S; Instituto de Investigaciones Sanitarias San Carlos (IdISSC), Madrid, Spain.
  • Mai A; Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, Italy.
  • Tripodi M; Division of Rheumatology, Ospedale Pediatrico Bambino Gesù IRCCS, Rome, Italy.
  • Strippoli R; Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz-Universidad Autónoma Madrid, Madrid, Spain.
Front Cell Infect Microbiol ; 14: 1308362, 2024.
Article em En | MEDLINE | ID: mdl-38476167
ABSTRACT
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 polyinosinicpolycytidylic acid (Poly(IC)), 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(IC) 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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Peritonite / Piridinas / Benzamidas / Viroses / Interferon Tipo I Limite: Humans Idioma: En Revista: Front Cell Infect Microbiol Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Itália

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Peritonite / Piridinas / Benzamidas / Viroses / Interferon Tipo I Limite: Humans Idioma: En Revista: Front Cell Infect Microbiol Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Itália