IRF1 is critical for the TNF-driven interferon response in rheumatoid fibroblast-like synoviocytes

Bonelli, Michael; Dalwigk, K; Platzer, Alexander; Calvo, Isabel Olmos; Hayer, Silvia; Niederreiter, Birgit; Holinka, Johannes; Sevelda, Florian; Pap, Thomas; Steiner, Günter; Superti‐Furga, Giulio; Smolen, Josef S; Kiener, Hans P.; Karonitsch, Thomas

doi:10.1038/s12276-019-0267-6

Cited by 58 publications

(66 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In line with this, silencing or the antibody-based neutralization of IFNβ significantly impaired the TNF-induced interferon response in synovial fibroblasts (57). Additionally, the silencing of IFNAR in synovial fibroblasts decreased pSTAT1 and reduced the expression of interferon response genes in the TNFstimulated synovial fibroblasts (57). Neutralizing anti-IFNAR antibodies prevented the TNF-induced production of IP-10 in human synovial fibroblasts and synovial fibroblasts from ifnar-/-mice did not upregulate IP-10 in response to TNF (50,57).…”

Section: Jakinibs Target the Tnf-induced Interferon Responses In Synosupporting

confidence: 58%

“…IFNβ activated STAT1 and the interferon response genes via human type I interferon receptor (IFNAR)-dependent signaling (Figure 1). In line with this, silencing or the antibody-based neutralization of IFNβ significantly impaired the TNF-induced interferon response in synovial fibroblasts (57). Additionally, the silencing of IFNAR in synovial fibroblasts decreased pSTAT1 and reduced the expression of interferon response genes in the TNFstimulated synovial fibroblasts (57).…”

Section: Jakinibs Target the Tnf-induced Interferon Responses In Synomentioning

confidence: 58%

“…The TNF stimulation of synovial fibroblasts led to an early induction of interferon response factor one (IRF1) protein followed by a delayed phosphorylation of STAT1 (Figure 1). Silencing of IRF1 or inhibition of de novo IRF1 synthesis by cycloheximide blocked the phosphorylation of STAT1 and reduced the TNF-driven expression of interferon response genes in synovial fibroblasts, including CXCL9, CXCL10, CXCL11, and BAFF (57). IRF1 was highly expressed in the synovium (54,57) of RA patients as well as TNF transgenic mice.…”

Section: Jakinibs Target the Tnf-induced Interferon Responses In Synomentioning

confidence: 99%

“…Silencing of IRF1 or inhibition of de novo IRF1 synthesis by cycloheximide blocked the phosphorylation of STAT1 and reduced the TNF-driven expression of interferon response genes in synovial fibroblasts, including CXCL9, CXCL10, CXCL11, and BAFF (57). IRF1 was highly expressed in the synovium (54,57) of RA patients as well as TNF transgenic mice. IRF1 was upregulated in synovial fibroblasts, cultured within the floating Matrigel microspheres, when treated with TNF (57).…”

Section: Jakinibs Target the Tnf-induced Interferon Responses In Synomentioning

confidence: 99%

“…IRF1 was highly expressed in the synovium (54,57) of RA patients as well as TNF transgenic mice. IRF1 was upregulated in synovial fibroblasts, cultured within the floating Matrigel microspheres, when treated with TNF (57). Overall, these experiments identified TNF as a major driver of synovial IRF1 expression, and the IRF1-pSTAT1 axis as a key regulator of the TNF-induced interferon gene signature in synovial fibroblasts (Figure 1).…”

Section: Jakinibs Target the Tnf-induced Interferon Responses In Synomentioning

confidence: 99%

See 4 more Smart Citations

Hi-JAKi-ng Synovial Fibroblasts in Inflammatory Arthritis With JAK Inhibitors

Burja

Mertelj²,

Frank-Bertoncelj³

2020

Front. Med.

View full text Add to dashboard Cite

The Janus kinase (JAK)-Signal transducer and activator of transcription (STAT) pathway is one of the central signaling hubs in inflammatory, immune and cancer cells. Inhibiting the JAK-STAT pathway with JAK inhibitors (jakinibs) constitutes an important therapeutic strategy in cancer and chronic inflammatory diseases like rheumatoid arthritis (RA). FDA has approved different jakinibs for the treatment of RA, including tofacitinib, baricitinib and upadacitinib, and several jakinibs are being tested in clinical trials. Here, we reviewed published studies of jakinib effects on resolving synovial pathology in inflammatory arthritis. We discussed the results of jakinibs on structural joint damage in clinical trials and explored the effects of jakinibs across different in vitro, ex vivo, and in vivo synovial experimental models. We delved rigorously into experimental designs of in vitro fibroblast studies, deconvoluted jakinib efficacy in synovial fibroblasts across diverse experimental conditions and discussed their translatability in vivo. Synovial fibroblasts can readily activate the JAK-STAT signaling pathway in response to cytokine stimulation. We highlighted rather limited effects of jakinibs on the in vitro cultured synovial fibroblasts and inferred that direct and indirect (immune cell-dependent) actions of jakinibs are required to curb the fibroblast pathology in vivo. These actions have not been mimicked optimally in current in vitro experimental designs, where inflammatory stimuli do not naturally clear out with treatment as they do in vivo. While summarizing the broad knowledge of synovial jakinib effects, our review uniquely challenges future study designs to better mimick the jakinib actions in broader cell communities, as occurring in vivo in the inflamed synovium. This can deepen our understanding of collective synovial activities of jakinibs and their therapeutic limitations, thereby fostering jakinib development in arthritis.

show abstract

Section: Jakinibs Target the Tnf-induced Interferon Responses In Synosupporting

confidence: 58%

Section: Jakinibs Target the Tnf-induced Interferon Responses In Synomentioning

confidence: 58%

Section: Jakinibs Target the Tnf-induced Interferon Responses In Synomentioning

confidence: 99%

Section: Jakinibs Target the Tnf-induced Interferon Responses In Synomentioning

confidence: 99%

Section: Jakinibs Target the Tnf-induced Interferon Responses In Synomentioning

confidence: 99%

See 3 more Smart Citations

Hi-JAKi-ng Synovial Fibroblasts in Inflammatory Arthritis With JAK Inhibitors

Burja

Mertelj²,

Frank-Bertoncelj³

2020

Front. Med.

View full text Add to dashboard Cite

show abstract

Role and Therapeutic Potential for Targeting Fibroblast Growth Factor 10/FGFR1 in Relapsed Rheumatoid Arthritis

Meng

Chen

et al. 2023

Arthritis & Rheumatology

View full text Add to dashboard Cite

ObjectivesFibroblast‐like synoviocytes (FLS) contribute to inflammation and joint damage in rheumatoid arthritis (RA). However, the regulatory mechanisms of FLS in relapse and remission RA remain unknown. Identifying FLS heterogeneity and their underlying pathogenic roles may lead to discovering novel disease‐modifying antirheumatic drugs.MethodsCombining single‐cell RNA‐sequencing (scRNA‐seq) and spatial transcriptomics, we sequenced six matched synovial tissue samples from three relapse RA patients and three patients in remission. We analyzed the differences in the transcriptomes of the FLS subsets between the relapse and remitted phases. We validated several key signaling pathways using qPCR and multiplex immunohistochemistry (HC). We further targeted the critical signals in vitro and in vivo using collage‐induced arthritis (CIA) model in rats.ResultsLining and sublining FLS subsets were identified using scRNA‐seq. Differential analyses indicated that the fibroblast growth factor (FGF) pathway was highly activated in the lining FLS from relapse RA patients where mIHC confirmed the increased expression of FGF10. While the type I interferon pathway was also activated in the lining FLS, in vitro stimulation experiment suggested that it was independent of the FGF10 pathway. FGF10 knockdown by siRNA in FLS significantly reduced the expression of RANKL. Moreover, recombinant FGF10 protein enhanced bone erosion in the primary human‐derived pannus cell culture, whereas the FGFR1 inhibitor attenuated this process. Finally, administering an FGFR1 inhibitor displayed a therapeutic effect in a CIA rat model.ConclusionThe FGF pathway is a critical signaling pathway in relapse RA. Targeted tissue‐specific inhibition of FGF10/FGFR1 may provide new opportunities to treat patients with relapse RA.

show abstract

Amino Acids Fueling Fibroblast‐Like Synoviocyte Activation and Arthritis By Regulating Chemokine Expression and Leukocyte Migration

Karonitsch,

Saferding,

Kieler

et al. 2024

Arthritis & Rheumatology

Self Cite

View full text Add to dashboard Cite

ObjectiveTo analyze the impact of amino acid (AA) availability on the inflammatory response in arthritis.MethodsWe stimulated rheumatoid arthritis (RA) fibroblast‐like synoviocytes (FLS) with TNF in the presence or absence of proteinogenic AAs and measured their response by QuantSeq 3′ mRNA sequencing, qPCR and ELISA. Signal transduction events were determined by Western Blot. We performed K/BxN serum transfer arthritis in mice receiving normal and a low protein diet and analyzed arthritis clinically and histologically.ResultsDeprivation of AAs decreased the expression of a specific subset of genes, including the chemokines CXCL10, CCL2 and CCL5 in TNF‐stimulated FLS. Mechanistically, the presence of AAs was required for the TNF‐induced activation of an IRF1‐STAT1 signaling circuit that drives the expression of chemotactic factors. The expression of IRF1 and the IRF1‐dependent gene set in FLS was highly correlated with the presence of inflammatory cells in human RA, emphasizing the important role of this AA‐dependent pathway in inflammatory cell recruitment to the synovial tissue. Finally, we show that mice receiving a low protein diet expressed less IRF1 in the inflamed synovium and consequently developed reduced clinical and histological signs of arthritis.ConclusionAA‐deprivation reduces the severity of arthritis by suppressing the expression of IRF1‐STAT1‐driven chemokines, which are crucial for leukocyte recruitment to the arthritic joint. Overall, our study provides novel insights into critical determinants of inflammatory arthritis and may pave the way for dietary intervention trials in RA.image

show abstract

IRF1 is critical for the TNF-driven interferon response in rheumatoid fibroblast-like synoviocytes

Cited by 58 publications

References 38 publications

Hi-JAKi-ng Synovial Fibroblasts in Inflammatory Arthritis With JAK Inhibitors

Hi-JAKi-ng Synovial Fibroblasts in Inflammatory Arthritis With JAK Inhibitors

Role and Therapeutic Potential for Targeting Fibroblast Growth Factor 10/FGFR1 in Relapsed Rheumatoid Arthritis

Amino Acids Fueling Fibroblast‐Like Synoviocyte Activation and Arthritis By Regulating Chemokine Expression and Leukocyte Migration

Contact Info

Product

Resources

About