Altered metabolic pathways regulate synovial inflammation in rheumatoid arthritis

Fearon, Ursula; Hanlon, Megan; Wade, Siobhan; Fletcher, Jean M.

doi:10.1111/cei.13228

Cited by 55 publications

(43 citation statements)

References 107 publications

(236 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The importance of metabolism in regulating synovial inflammation has recently emerged with many studies indicating that immune and stromal cells undergo a bioenergetic switch to a highly metabolically active state in order to meet the energy demands of the expanding synovium (7, 8). Indeed, the metabolic milieu of the inflamed joint reflects the chronically active state of immune and stromal cells, with elevated lactate levels and reduced glucose observed in RA synovial fluid, along with increased glycolytic enzyme activity and accumulation of succinate in synovial fluid and tissue (9–13).…”

Section: Introductionmentioning

confidence: 99%

STAT3 Mediates the Differential Effects of Oncostatin M and TNFα on RA Synovial Fibroblast and Endothelial Cell Function

et al. 2019

View full text Add to dashboard Cite

Objectives: Oncostatin M (OSM), a pleiotropic cytokine and a member of the gp130/IL-6 cytokine family, has been implicated in the pathogenesis of autoimmune diseases. Here we investigate the mechanisms by which its synergistic interactions with TNFα regulate the cellular bioenergetics and invasive function of synovial cells from patients with Rheumatoid Arthritis. Methods: Primary RA synovial fibroblasts (RAFLS) and human umbilical vein endothelial cells (HUVEC) were cultured with OSM alone or in combination with TNFα. Pro-inflammatory cytokines, angiogenic growth factors and adhesion molecules were quantified by real-time PCR and ELISA. Invasion, angiogenesis and cellular adhesion were quantified by Transwell invasion chambers, Matrigel tube formation assays, and adhesion binding assays. Cellular bioenergetics was assessed using the Seahorse XFe96 Analyser. Key metabolic genes (GLUT-1, HK2, PFKFB3, HIF1α, LDHA, PKM2) and transcription factor STAT3 were measured using real-time PCR and western blot. Results: OSM differentially regulates pro-inflammatory mediators in RAFLS and HUVEC, with IL-6, MCP-1, ICAM-1, and VEGF all significantly induced, in contrast to the observed inhibition of IL-8 and GROα, with opposing effects observed for VCAM-1 depending on cell type. Functionally, OSM significantly induced angiogenic network formation, adhesion, and invasive mechanisms. This was accompanied by a change in the cellular bioenergetic profile of the cells, where OSM significantly increased the ECAR/OCR ratio in favor of glycolysis, paralleled by induction of the glucose transporter GLUT-1 and key glycolytic enzymes (HK2, PFKFB3, HIF1α). OSM synergizes with TNFα to differentially regulate pro-inflammatory mechanisms in RAFLS and HUVEC. Interestingly, OSM differentially synergizes with TNFα to regulate metabolic reprogramming, where induction of glycolytic activity with concomitant attenuation of mitochondrial respiration and ATP activity was demonstrated in RAFLS but not in HUVEC. Finally, we identified a mechanism, whereby the combination of OSM with TNFα induces transcriptional activity of STAT3 only in RAFLS, with no effect observed in HUVEC. Conclusion: STAT3 mediates the differential effects of OSM and TNFα on RAFLS and EC function. Targeting OSM or downstream signaling pathways may lead to new potential therapeutic or adjuvant strategies, particularly for those patients who have sub-optimal responses to TNFi.

show abstract

Section: Introductionmentioning

confidence: 99%

STAT3 Mediates the Differential Effects of Oncostatin M and TNFα on RA Synovial Fibroblast and Endothelial Cell Function

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Macrophages constitute the dominant immune cell population in the inflamed joint and the major producer of inflammatory cytokines, including TNF-α, IL-6, and IL-1β. In RA, macrophages undergo a metabolic switch from oxidative phosphorylation to glycolysis resulting in activation of the proinflammatory transcription factors such as HIF-1α, STAT3 and NF-kB, and increased production of inflammatory cytokines [24–26]. An important bi-directional cross-talk between synovial fibroblasts and macrophages contributing to the disease pathogenesis has been recently described [27].…”

Section: Introductionmentioning

confidence: 99%

Active roles of dysfunctional vascular endothelium in fibrosis and cancer

Hsu¹,

Nguyen-Tran²,

Trojanowska

2019

J Biomed Sci

View full text Add to dashboard Cite

Chronic inflammation is the underlying pathological condition that results in fibrotic diseases. More recently, many forms of cancer have also been linked to chronic tissue inflammation. While stromal immune cells and myofibroblasts have been recognized as major contributors of cytokines and growth factors that foster the formation of fibrotic tissue, the endothelium has traditionally been regarded as a passive player in the pathogenic process, or even as a barrier since it provides a physical divide between the circulating immune cells and the inflamed tissues. Recent findings, however, have indicated that endothelial cells in fact play a crucial role in the inflammatory response. Endothelial cells can be activated by cytokine signaling and express inflammatory markers, which can sustain or exacerbate the inflammatory process. For example, the activated endothelium can recruit and activate leukocytes, thus perpetuating tissue inflammation, while sustained stimulation of endothelial cells may lead to endothelial-to-mesenchymal transition that contributes to fibrosis. Since chronic inflammation has now been recognized as a significant contributing factor to tumorigenesis, it has also emerged that activation of endothelium also occurs in the tumor microenvironment. This review summarizes recent findings characterizing the molecular and cellular changes in the vascular endothelium that contribute to tissue fibrosis, and potentially to cancer formation.

show abstract

“…This inactivation of pathways involved in metabolism among responders corroborates with the previous ndings that proliferation and rapid activation of immune and stromal cells requires a metabolically highly active state. Such a high metabolic state induces overproduction of enzymes that lead to degradation of cartilage and bones and the production of cytokines that promote immune cell in ltration [40][41][42].…”

Section: Discussionmentioning

confidence: 99%

Molecular Biomarkers of Anti-TNF Response in Patients with Rheumatoid Arthritis

Yoosuf

Maciejewski

Ziemek

et al. 2020

Preprint

View full text Add to dashboard Cite

BackgroundAdvances in immunotherapy by blocking TNF have remarkably improved treatment outcomes for rheumatoid arthritis (RA) patients. Although treatment specifically targets TNF-α, the downstream mechanisms of immune suppression are not completely understood, and the reason for the reduced efficacy in a significant fraction of patients remains unclear. Hence this study was designed to detect biomarkers and expression signatures of response to TNF inhibition.MethodsIn this study, we included 39 female patients diagnosed with RA who were non-responders to methotrexate treatment. The blood samples were collected before anti-TNF treatment initiation, and three months into treatment. The clinical evaluations were performed based on European League Against Rheumatism (EULAR) and classified 23 patients as responders and 16 as non-responders after three months following the initiation of anti-TNF treatment. We investigated differences in gene expression in peripheral blood mononuclear cells (PBMCs), the proportion of cell types and cell phenotypes in peripheral blood using flow cytometry, the level of proteins in serum, as well as clinical and demographic factors.ResultsWe performed analyses to identify differences between responders and non-responders at both time points (before and after treatment initiation) as well as to detect the changes induced during the treatment using transcriptomics, flow cytometry and proteomics data. The gene expression analysis before treatment revealed notably a higher expression of EPPK1 and BCL6-AS1 in future responders. We further detected suppression of genes and proteins during treatment, most notably a suppression of expression of the gene, T-cell inhibitor CHI3L1 and its protein YKL-40 measured from flow cytometry. We identified an increase in the proportion of T- and B cells, whereas the proportion of granulocytes was suppressed during treatment in responders. Finally, our machine learning models mainly based on transcriptomics data showed high predictive utility (ROC AUC ± SEM: 0.81 ± 0.17) in classifying response before anti-TNF treatment initiation.ConclusionsOur comprehensive analyses resulted in several useful insights regarding the transcriptional and translational regulations of anti-TNF treatment in RA patients. The study reports first transcriptomics analysis using RNA sequencing of isolated PBMCs from anti-TNF naïve and anti-TNF treated RA patients to study biomarkers and predict anti-TNF response.

show abstract

Altered metabolic pathways regulate synovial inflammation in rheumatoid arthritis

Cited by 55 publications

References 107 publications

STAT3 Mediates the Differential Effects of Oncostatin M and TNFα on RA Synovial Fibroblast and Endothelial Cell Function

STAT3 Mediates the Differential Effects of Oncostatin M and TNFα on RA Synovial Fibroblast and Endothelial Cell Function

Active roles of dysfunctional vascular endothelium in fibrosis and cancer

Molecular Biomarkers of Anti-TNF Response in Patients with Rheumatoid Arthritis

Contact Info

Product

Resources

About