Characterization of long non-coding rnas in systemic sclerosis monocytes: A potential role for psmb8-as1 in altered cytokine secretion
Servaas, Nila H.; Mariotti, Barbara; van der Kroef, Maarten; Wichers, Catharina G.K.; Pandit, Aridaman; Bazzoni, Flavia; Radstake, Timothy R.D.J.; Rossato, Marzia
(2021) International Journal of Molecular Sciences, volume 22, issue 9, pp. 1 - 18
(Article)
Abstract
Systemic sclerosis (SSc) is a chronic autoimmune disease mainly affecting the connective tissue. In SSc patients, monocytes are increased in circulation, infiltrate affected tissues, and show a pro-inflammatory activation status, including the so-called interferon (IFN) signature. We previously demonstrated that the dysregulation of the IFN response in SSc monocytes is
... read more
sustained by altered epigenetic factors as well as by upregulation of the long non-coding RNA (lncRNA) NRIR. Considering the enormously diverse molecular functions of lncRNAs in immune regulation, the present study investigated the genome-wide profile of lncRNAs in SSc monocytes, with the aim to further unravel their possible role in monocyte dysregulation and disease pathogenesis. Transcriptomic data from two independent cohorts of SSc patients identified 886 lncRNAs with an altered expression in SSc monocytes. Differentially expressed lncRNAs were correlated with neighboring protein coding genes implicated in the regulation of IFN responses and apoptotic signaling in SSc monocytes. In parallel, gene co-expression network analysis identified the lncRNA PSMB8-AS1 as a top-ranking hub gene in co-expression modules implicated in cell activation and response to viral and external stimuli. Functional characterization of PSMB8-AS1 in monocytes demonstrated that this lncRNA is involved in the secretion of IL-6 and TNFα, two pivotal pro-inflammatory cytokines altered in the circulation of SSc patients and associated with fibrosis and disease severity. Collectively, our data showed that lncRNAs are linked to monocyte dysregulation in SSc, and highlight their potential contribution to disease pathogenesis.
show less
Download/Full Text
Keywords: monocytes, systemic sclerosis, autoimmune, long non-coding RNA, co-expression network, Scleroderma, Systemic/genetics, Humans, Middle Aged, Transcriptome, Male, Case-Control Studies, RNA, Long Noncoding/genetics, Adult, Female, Aged, Cytokines/metabolism, RNA, Antisense/genetics, Proteasome Endopeptidase Complex/chemistry, Monocytes/metabolism, Molecular Biology, Spectroscopy, Catalysis, Inorganic Chemistry, Computer Science Applications, Physical and Theoretical Chemistry, Organic Chemistry, Journal Article
ISSN: 1661-6596
Publisher: Multidisciplinary Digital Publishing Institute (MDPI)
Note: Funding Information: Funding: F.B. was funded by Joint Project 2017 (JPVR2017), Ateneo di Verona, Progetti di Ricerca di Interesse Nazionale (PRIN2017, Prot. 20174T7NXL), and by Fondazione CARIPLO (2015-0584). M.R. was funded by the Dutch Arthritis Foundation (Reuma Nederland, grant number NR14-3-403). T.R.D.J.R was funded by the ERC starting grant (ERC-2011-StG, Circum-vent). Funding Information: F.B. was funded by Joint Project 2017 (JPVR2017), Ateneo di Verona, Progetti di Ricerca di Interesse Nazionale (PRIN2017, Prot. 20174T7NXL), and by Fondazione CARIPLO (2015-0584). M.R. was funded by the Dutch Arthritis Foundation (Reuma Nederland, grant number NR14-3-403). T.R.D.J.R was funded by the ERC starting grant (ERC-2011-StG, Circum-vent).We thank the SSc isolation team from the University Medical Centre Utrecht for their contributions to the sample collection from SSc patients. Furthermore, we thank E. Ton and J.M. van Laar from the Department of Rheumatology & Clinical Immunology in University Medical Centre Utrecht for their help with patient inclusion. We are grateful to all of the patients and healthy controls who participated in this study. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
(Peer reviewed)
