TY - JOUR
T1 - Characterization of long non-coding rnas in systemic sclerosis monocytes
T2 - A potential role for psmb8-as1 in altered cytokine secretion
AU - Servaas, Nila H.
AU - Mariotti, Barbara
AU - van der Kroef, Maarten
AU - Wichers, Catharina G.K.
AU - Pandit, Aridaman
AU - Bazzoni, Flavia
AU - Radstake, Timothy R.D.J.
AU - Rossato, Marzia
N1 - 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.
PY - 2021/4/22
Y1 - 2021/4/22
N2 - 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 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.
AB - 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 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.
KW - monocytes
KW - systemic sclerosis
KW - autoimmune
KW - long non-coding RNA
KW - co-expression network
KW - Scleroderma, Systemic/genetics
KW - Humans
KW - Middle Aged
KW - Transcriptome
KW - Male
KW - Case-Control Studies
KW - RNA, Long Noncoding/genetics
KW - Adult
KW - Female
KW - Aged
KW - Cytokines/metabolism
KW - RNA, Antisense/genetics
KW - Proteasome Endopeptidase Complex/chemistry
KW - Monocytes/metabolism
UR - http://www.scopus.com/inward/record.url?scp=85104516027&partnerID=8YFLogxK
U2 - 10.3390/ijms22094365
DO - 10.3390/ijms22094365
M3 - Article
C2 - 33922041
AN - SCOPUS:85104516027
SN - 1661-6596
VL - 22
SP - 1
EP - 18
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 9
M1 - 4365
ER -