Silvia Borghini1, Denise Ferrera2, Ignazia Prigione3, Michele Fiore2, Chiara Ferraris2, Valentina Mirisola4, Adriana Agnese Amaro4, Ilaria Gueli5, Luca Zammataro6, Marco Gattorno5, Ulrich Pfeffer4, Isabella Ceccherini7. 1. U.O. Genetica Medica, Istituto G. Gaslini, Genova, Italy. s.borghini@unige.it. 2. U.O. Genetica Medica, Istituto G. Gaslini, Genova, Italy. 3. Laboratorio di Oncologia, Istituto G. Gaslini, Genova, Italy. 4. Molecular Pathology, IRCCS A.O.U. San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy. 5. U.O. Pediatria II-Reumatologia and Laboratorio di Immunologia delle Malattie Reumatiche, Istituto G. Gaslini, Genova, Italy. 6. Computational Research, Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milano, Italy. 7. U.O. Genetica Medica, Istituto G. Gaslini, Genova, Italy. isa.c@unige.it.
Abstract
OBJECTIVES: Tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is a multisystemic autoinflammatory condition associated with heterozygous TNFRSF1A mutations, presenting with a variety of clinical symptoms, many of which yet unexplained. In this work, we aimed at deepening into TRAPS pathogenic mechanisms sustained by monocytes. METHODS: Microarray experiments were conducted to identify genes whose expression results altered in patients compared to healthy individuals, both under basal condition and following LPS stimulation. RESULTS: An inflammatory state baseline, characterised by constitutive overexpression of IL1β and IL1R1 receptor, has been shown in TRAPS patients compared to controls, including in non-active disease phases. Following LPS stimulation, IL1RN up-regulation is stronger in controls than in patients and inflammatory pathways and microRNAs undergo differential regulation. Genes involved in post-translational modifications, protein folding and ubiquitination result constitutively up-regulated in TRAPS, while response to interferon types I and II is defective, failing to be up-regulated by LPS. TGFβ pathway is down-regulated in untreated TRAPS monocytes, while genes involved in redox regulation result constitutively over-expressed. Finally, additional molecular alterations seem to reflect organ failures sometime complicating the disease. CONCLUSIONS: Gene expression profile in resting TRAPS monocytes has confirmed the patients' chronic inflammatory condition. In addition, pathways not yet associated with the disease have been disclosed, such as interferon types I and II response to LPS stimulation and a downregulation of the TGFβ pathway in basal condition. The role of miRNA, suggested by our results, deserves in-depth analyses in light of the possible development of targeted therapies.
OBJECTIVES:Tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is a multisystemic autoinflammatory condition associated with heterozygous TNFRSF1A mutations, presenting with a variety of clinical symptoms, many of which yet unexplained. In this work, we aimed at deepening into TRAPS pathogenic mechanisms sustained by monocytes. METHODS: Microarray experiments were conducted to identify genes whose expression results altered in patients compared to healthy individuals, both under basal condition and following LPS stimulation. RESULTS: An inflammatory state baseline, characterised by constitutive overexpression of IL1β and IL1R1 receptor, has been shown in TRAPS patients compared to controls, including in non-active disease phases. Following LPS stimulation, IL1RN up-regulation is stronger in controls than in patients and inflammatory pathways and microRNAs undergo differential regulation. Genes involved in post-translational modifications, protein folding and ubiquitination result constitutively up-regulated in TRAPS, while response to interferon types I and II is defective, failing to be up-regulated by LPS. TGFβ pathway is down-regulated in untreated TRAPS monocytes, while genes involved in redox regulation result constitutively over-expressed. Finally, additional molecular alterations seem to reflect organ failures sometime complicating the disease. CONCLUSIONS: Gene expression profile in resting TRAPS monocytes has confirmed the patients' chronic inflammatory condition. In addition, pathways not yet associated with the disease have been disclosed, such as interferon types I and II response to LPS stimulation and a downregulation of the TGFβ pathway in basal condition. The role of miRNA, suggested by our results, deserves in-depth analyses in light of the possible development of targeted therapies.
Authors: Antonio Vitale; Laura Obici; Marco Cattalini; Giuseppe Lopalco; Giampaolo Merlini; Nicola Ricco; Alessandra Soriano; Francesco La Torre; Elena Verrecchia; Antonella Insalaco; Lorenzo Dagna; Masen Abdel Jaber; Davide Montin; Giacomo Emmi; Luisa Ciarcia; Sara Barneschi; Paola Parronchi; Piero Ruscitti; Maria Cristina Maggio; Ombretta Viapiana; Jurgen Sota; Carla Gaggiano; Roberto Giacomelli; Ludovico Luca Sicignano; Raffaele Manna; Alessandra Renieri; Caterina Lo Rizzo; Bruno Frediani; Donato Rigante; Luca Cantarini Journal: Front Med (Lausanne) Date: 2021-07-08
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