A comprehensive transcriptomic analysis of alternate interferon signaling pathways in peripheral blood mononuclear cells in rheumatoid arthritis

Liang, Han; Tu, Shenghao; Shen, Pan; Yan, Jiahui; Huang, Yao; Ba, Xin; Li, Tingting; Lin, Wei Chen; Li, Huihui; Yu, Kun; Guo, Jing; Huang, Ying; Wang, Yu; Chen, Zhe

doi:10.18632/aging.203432

Cited by 6 publications

(3 citation statements)

References 82 publications

(93 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…MEFs were cultured in DMEM containing 10% FBS and were used within passage 5 for this study. Peripheral blood mononuclear cells (PBMCs) and lymphocytes were obtained from peripheral blood as described previously ( 24 ). To generate PBMCs derived macrophages, PBMSs was cultured in RPMI 1640 media containing 10% FBS and 20 ng/mL GM-CSF((Peprotech, Rocky Hill, NJ, USA)) for 5 days.…”

Section: Methodsmentioning

confidence: 99%

ATF6α contributes to rheumatoid arthritis by inducing inflammatory cytokine production and apoptosis resistance

Wang

Shi

et al. 2022

Front. Immunol.

View full text Add to dashboard Cite

ObjectiveThe contribution of activating transcription factor 6α (ATF6α) in rheumatoid arthritis (RA) pathogenesis, especially on fibroblast-like synoviocytes (FLSs), has been suggested by its sensitivity to inflammatory stimulus. However, the exact role and therapeutic potential of ATF6α in RA remains to be fully elucidated.MethodsATF6α expression was determined in joint tissues and FLS, and gain-of-function and loss-of-function analyses were applied to evaluate the biological roles of ATF6α in RA FLSs. A murine collagen-induced arthritis (CIA) model, combining both gene deletion of ATF6α and treatment with the ATF6α inhibitor Ceapin-A7, was employed. Joint inflammation, tissue destruction, circulating levels of inflammatory cytokines were assessed in CIA mice. Transcriptome sequencing analysis (RNASeq), molecular biology, and biochemical approaches were performed to identify target genes of ATF6α.ResultsATF6α expression was significantly increased in synovium of RA patients and in synovium of mice subjected to CIA. ATF6α silencing or inhibition repressed RA FLSs viability and cytokine production but induced the apoptosis. CIA-model mice with ATF6α deficiency displayed decreased arthritic progression, leading to profound reductions in clinical and proinflammatory markers in the joints. Pharmacological treatment of mice with Ceapin-A7 reduced arthritis severity in CIA models. RNA-sequencing of wild-type and knockdown of ATF6α in RA FLSs revealed a transcriptional program that promotes inflammation and suppresses apoptosis, and subsequent experiments identified Baculoviral IAP Repeat Containing 3 (BIRC3) as the direct target for ATF6α.ConclusionThis study highlights the pathogenic role of ATF6α-BIRC3 axis in RA and identifies a novel pathway for new therapies against RA.

show abstract

Section: Methodsmentioning

confidence: 99%

ATF6α contributes to rheumatoid arthritis by inducing inflammatory cytokine production and apoptosis resistance

Wang

Shi

et al. 2022

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…In keeping with this differential ERE expression, there was increased IFNA transcript in RA naïve B cells. Single cell analysis of RA circulating B cell subsets previously demonstrated increased sensitivity to IFN-α and increased IFNA transcript in RA naïve B cells, resulting in increased basal activation and proliferation (47). The role of IFN-α in B cell function and pathophysiology of autoimmunity has been well established whereby it can enhance B cell proliferation, activation and autoantibody production (3).…”

Section: Discussionmentioning

confidence: 99%

Endogenous retroelement activation is implicated in IFN-α production and anti-CCP autoantibody generation in early RA

Cooles,

Pedrola,

Naamane

et al. 2024

Preprint

View full text Add to dashboard Cite

Objectives: Endogenous retroelements (EREs) stimulate type 1 interferon (IFN-I) production but have not been explored as potential interferonogenic triggers in Rheumatoid Arthritis (RA). We investigated ERE expression in early RA (eRA), a period where IFN-I is increased. Methods: ERE expression in DMARD naive eRA whole blood (LINE1, RT-PCR) and bulk synovial tissue (LTR5, LINE1, SINE, Nanostring) was examined alongside IFN-alpha activity. Circulating lymphocyte subsets, including B cell subsets, from eRA patients and early psoriatic arthritis (PsA), were flow cytometrically sorted and similarly examined. Existing established RA and osteoarthritis (OA) synovial single-cell sequencing data was re-interrogated to identify repeat elements, and associations explored. Results: There was significant co-expression of all ERE classes and IFNA in eRA synovial tissue (n=22, p<0.0001) and significant positive associations between whole blood LINE1 expression (n=56) and circulating IFN-protein (p=0.018) and anti-CCP titres (p<0.0001). ERE expression was highest in circulating eRA B cells, particularly naive B cells compared with PsA, with ERE regulation by SAMDH1 implicated and associations with IFNA again observed. Finally, in established RA synovium, LTRs, particularly ERVK, were most increased in RA compared with OA where, for all synovial subsets (monocytes, B cells, T cells and fibroblasts), ERE expression associated with increased IFN-I signalling (p<0.001). Conclusions: Peripheral blood and synovial ERE expression is examined for the first time in eRA highlighting both a potential causal relationship between ERE and IFN-I production and an intriguing association with anti-CCP autoantibodies. This suggests EREs may contribute to RA pathophysiology with implications for future novel therapeutic strategies.

show abstract

“… 81 As shown by Fonseka et al 82 , CD27 - HLA - DR + effector memory cells with Th1 - and cytotoxicity-associated features were enriched at the primary sites of inflammation and were related to the efficacy of treatment. Han et al 83 observed a connection between active IFN signaling pathways and disease promotion by CD56 bright and CD56 dim NK cells in subjects with RA. Activation of the type I IFN signaling pathway might generate the inflammatory signaling amplifier CH25H.…”

Section: Introductionmentioning

confidence: 99%

Single-cell RNA sequencing in orthopedic research

et al. 2023

View full text Add to dashboard Cite

Although previous RNA sequencing methods have been widely used in orthopedic research and have provided ideas for therapeutic strategies, the specific mechanisms of some orthopedic disorders, including osteoarthritis, lumbar disc herniation, rheumatoid arthritis, fractures, tendon injuries, spinal cord injury, heterotopic ossification, and osteosarcoma, require further elucidation. The emergence of the single-cell RNA sequencing (scRNA-seq) technique has introduced a new era of research on these topics, as this method provides information regarding cellular heterogeneity, new cell subtypes, functions of novel subclusters, potential molecular mechanisms, cell-fate transitions, and cell‒cell interactions that are involved in the development of orthopedic diseases. Here, we summarize the cell subpopulations, genes, and underlying mechanisms involved in the development of orthopedic diseases identified by scRNA-seq, improving our understanding of the pathology of these diseases and providing new insights into therapeutic approaches.

show abstract

A comprehensive transcriptomic analysis of alternate interferon signaling pathways in peripheral blood mononuclear cells in rheumatoid arthritis

Cited by 6 publications

References 82 publications

ATF6α contributes to rheumatoid arthritis by inducing inflammatory cytokine production and apoptosis resistance

ATF6α contributes to rheumatoid arthritis by inducing inflammatory cytokine production and apoptosis resistance

Endogenous retroelement activation is implicated in IFN-α production and anti-CCP autoantibody generation in early RA

Single-cell RNA sequencing in orthopedic research

Contact Info

Product

Resources

About