scholarly journals HBEGF+ macrophages identified in rheumatoid arthritis promote joint tissue invasiveness and are reshaped differentially by medications

2019 ◽  
Author(s):  
David Kuo ◽  
Jennifer Ding ◽  
Ian Cohn ◽  
Fan Zhang ◽  
Kevin Wei ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Egf Receptor ◽  
Wide Spectrum ◽  
Joint Destruction ◽  
Human Macrophage ◽  
Dependent Manner ◽  
Human Tissues ◽  
Joint Tissue ◽  
Macrophage Phenotypes ◽  
Anti Inflammatory

AbstractMacrophages tailor their function to the signals found in tissue microenvironments, taking on a wide spectrum of phenotypes. In human tissues, a detailed understanding of macrophage phenotypes is limited. Using single-cell RNA-sequencing, we define distinct macrophage subsets in the joints of patients with the autoimmune disease rheumatoid arthritis (RA), which affects ~1% of the population. The subset we refer to as HBEGF+ inflammatory macrophages is enriched in RA tissues and shaped by resident fibroblasts and the cytokine TNF. These macrophages promote fibroblast invasiveness in an EGF receptor dependent manner, indicating that inflammatory intercellular crosstalk reshapes both cell types and contributes to fibroblast-mediated joint destruction. In an ex vivo tissue assay, the HBEGF+ inflammatory macrophage is targeted by several anti-inflammatory RA medications, however, COX inhibition redirects it towards a different inflammatory phenotype that is also expected to perpetuate pathology. These data highlight advances in understanding the pathophysiology and drug mechanisms in chronic inflammatory disorders can be achieved by focusing on macrophage phenotypes in the context of complex interactions in human tissues.One Sentence SummaryA newly identified human macrophage phenotype from patients with the autoimmune condition RA is found to promote joint tissue invasiveness and demonstrates variable sensitivities to anti-inflammatory medications used to treat the disease.

scholarly journals HBEGF+ macrophages in rheumatoid arthritis induce fibroblast invasiveness

2019 ◽  
Vol 11 (491) ◽  
pp. eaau8587 ◽  
Author(s):  
David Kuo ◽  
Jennifer Ding ◽  
Ian S. Cohn ◽  
Fan Zhang ◽  
Kevin Wei ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Ex Vivo ◽  
Wide Spectrum ◽  
Joint Destruction ◽  
Growth Factor Receptor ◽  
Cell Types ◽  
Dependent Manner ◽  
Human Tissues ◽  
Macrophage Phenotypes ◽  
Inflammatory Macrophages

Macrophages tailor their function according to the signals found in tissue microenvironments, assuming a wide spectrum of phenotypes. A detailed understanding of macrophage phenotypes in human tissues is limited. Using single-cell RNA sequencing, we defined distinct macrophage subsets in the joints of patients with the autoimmune disease rheumatoid arthritis (RA), which affects ~1% of the population. The subset we refer to as HBEGF+ inflammatory macrophages is enriched in RA tissues and is shaped by resident fibroblasts and the cytokine tumor necrosis factor (TNF). These macrophages promoted fibroblast invasiveness in an epidermal growth factor receptor–dependent manner, indicating that intercellular cross-talk in this inflamed setting reshapes both cell types and contributes to fibroblast-mediated joint destruction. In an ex vivo synovial tissue assay, most medications used to treat RA patients targeted HBEGF+ inflammatory macrophages; however, in some cases, medication redirected them into a state that is not expected to resolve inflammation. These data highlight how advances in our understanding of chronically inflamed human tissues and the effects of medications therein can be achieved by studies on local macrophage phenotypes and intercellular interactions.

scholarly journals Arthritis and the role of endogenous glucocorticoids

Bone Research ◽  
2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Eugenie Macfarlane ◽  
Markus J. Seibel ◽  
Hong Zhou
Keyword(s):  
Rheumatoid Arthritis ◽  
Joint Destruction ◽  
Degenerative Joint Disease ◽  
Joint Disease ◽  
Current Evidence ◽  
Inflammatory Microenvironment ◽  
Glucocorticoid Signaling ◽  
Anti Inflammatory ◽  
Fibroblast Like Synoviocytes

Abstract Rheumatoid arthritis and osteoarthritis, the most common forms of arthritis, are chronic, painful, and disabling conditions. Although both diseases differ in etiology, they manifest in progressive joint destruction characterized by pathological changes in the articular cartilage, bone, and synovium. While the potent anti-inflammatory properties of therapeutic (i.e., exogenous) glucocorticoids have been heavily researched and are widely used in clinical practice, the role of endogenous glucocorticoids in arthritis susceptibility and disease progression remains poorly understood. Current evidence from mouse models suggests that local endogenous glucocorticoid signaling is upregulated by the pro-inflammatory microenvironment in rheumatoid arthritis and by aging-related mechanisms in osteoarthritis. Furthermore, these models indicate that endogenous glucocorticoid signaling in macrophages, mast cells, and chondrocytes has anti-inflammatory effects, while signaling in fibroblast-like synoviocytes, myocytes, osteoblasts, and osteocytes has pro-inflammatory actions in rheumatoid arthritis. Conversely, in osteoarthritis, endogenous glucocorticoid signaling in both osteoblasts and chondrocytes has destructive actions. Together these studies provide insights into the role of endogenous glucocorticoids in the pathogenesis of both inflammatory and degenerative joint disease.

scholarly journals Identification of small molecule inhibitors of RANKL and TNF signalling as anti-inflammatory and antiresorptive agents in mice

2013 ◽  
Vol 74 (1) ◽  
pp. 220-226 ◽  
Author(s):  
Emmanuel Coste ◽  
Iain R Greig ◽  
Patrick Mollat ◽  
Lorraine Rose ◽  
Mohini Gray ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Bone Loss ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Joint Destruction ◽  
Luciferase Reporter ◽  
Collagen Induced Arthritis ◽  
Arthritis Model ◽  
Anti Inflammatory ◽  
Systemic Bone Loss

IntroductionInflammatory joint diseases such as rheumatoid arthritis are associated with local bone erosions and systemic bone loss, mediated by increased osteoclastic activity. The receptor activator of nuclear factor (NF) κB ligand (RANKL) plays a key role in mediating inflammation-induced bone loss, whereas tumour necrosis factor (TNF) plays a central role in the inflammatory process. Here we tested whether a recently identified class of small molecule inhibitors of RANKL signalling (ABD compounds) also affect TNF signalling and whether these compounds inhibit inflammation in an animal model of rheumatoid arthritis.MethodsThe inhibitory effects of the ABD compounds on TNF-induced signalling were tested in mouse macrophage cultures by western blotting and in an NFκB luciferase-reporter cell line. The anti-inflammatory effects of the compounds were tested in the mouse collagen-induced arthritis model of rheumatoid arthritis.ResultsThe ABD compounds ABD328 and ABD345 both inhibited TNF-induced activation of the NFκB pathway and the extracellular signal-regulated kinase (ERK) and Jun kinase (JNK) mitogen activated protein kinases (MAPKs). When tested in the mouse collagen-induced arthritis model of rheumatoid arthritis, the compounds suppressed inflammatory arthritis, inhibited joint destruction and prevented systemic bone loss. Furthermore, one of the compounds (ABD328) showed oral activity.ConclusionsHere we describe a novel class of small molecule compounds that inhibit both RANKL- and TNF-induced NFκB and MAPK signalling in osteoclasts and macrophages, and inflammation and bone destruction in a mouse model of rheumatoid arthritis. These novel compounds therefore represent a promising new class of treatments for inflammatory diseases, such as rheumatoid arthritis.

scholarly journals Sustained Hypoxia Suppresses Joint Destruction in a Rat Model of Rheumatoid Arthritis via Negative Feedback of Hypoxia Inducible Factor-1α

2021 ◽  
Vol 22 (8) ◽  
pp. 3898
Author(s):  
Kenta Kaihara ◽  
Shuji Nakagawa ◽  
Yuji Arai ◽  
Hiroaki Inoue ◽  
Shinji Tsuchida ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Inflammatory Cytokines ◽  
Joint Destruction ◽  
Hypoxia Inducible Factor ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Collagen Induced Arthritis ◽  
Risk Patients ◽  
Sustained Hypoxia ◽  
Pro Inflammatory Cytokines

Hypoxia inducible factor (HIF)-1α has been implicated in the pathogenesis of rheumatoid arthritis (RA). HIF-1α, which is expressed in hypoxia, is reversely suppressed in sustained hypoxia. Here, we investigated the inhibitory effect of hypoxia on arthritis by controlling HIF-1α. Rheumatoid fibroblast-like synoviocyte MH7A cells were cultured in a hypoxic incubator for up to 72 h to evaluate the expression of HIF-1. Furthermore, collagen-induced arthritis (CIA) model rats were maintained under 12% hypoxia in a hypoxic chamber for 28 days to evaluate the effect on arthritis. In MH7A cells, HIF-1α protein level increased at 3 h, peaked at 6 h, and subsequently decreased in a time-dependent manner. The transcription of pro-inflammatory cytokines increased at 1 h; however, they decreased after 3 h (p < 0.05). Deferoxamine-mediated activation of HIF-1α abolished the inhibitory effect of sustained hypoxia on pro-inflammatory cytokines. In the rat CIA model, the onset of joint swelling was delayed and arthritis was suppressed in the hypoxia group compared with the normoxia group (p < 0.05). Histologically, joint destruction was suppressed primarily in the cartilage. Thus, sustained hypoxia may represent a new safe, and potent therapeutic approach for high-risk patients with RA by suppressing HIF-1α expression.

scholarly journals Scropolioside B Inhibits IL-1βand Cytokines Expression through NF-κB and Inflammasome NLRP3 Pathways

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Tiantian Zhu ◽  
Liuqiang Zhang ◽  
Shuang Ling ◽  
Ju Duan ◽  
Fei Qian ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Protein Level ◽  
Vascular Diseases ◽  
Chronic Illnesses ◽  
Tibetan Medicine ◽  
Dependent Manner ◽  
Potential Drug ◽  
Inflammatory Mechanism ◽  
Anti Inflammatory ◽  
Dose Dependent

Chronic inflammation is associated with various chronic illnesses including immunity disorders, cancer, neurodegeneration, and vascular diseases. Iridoids are compounds with anti-inflammatory properties. However their anti-inflammatory mechanism remains unclear. Here, we report that scropolioside B, isolated from a Tibetan medicine (Scrophularia dentataRoyle ex Benth.), blocked expressions of TNF, IL-1, and IL-32 through NF-κB pathway. Scropolioside B inhibited NF-κB activity in a dose-dependent manner with IC50values of 1.02 μmol/L. However, catalpol, similar to scropolioside B, was not effective in inhibiting NF-κB activity. Interestingly, scropolioside B and catalpol decreased the expression of NLRP3 and cardiolipin synthetase at both the mRNA and protein level. Our results showed that scropolioside B is superior in inhibiting the expression, maturation, and secretion of IL-1βcompared to catalpol. These observations provide further understanding of the anti-inflammatory effects of iridoids and highlight scropolioside B as a potential drug for the treatment of rheumatoid arthritis and atherosclerosis.

scholarly journals The Janus kinase 1/2 inhibitor baricitinib reduces biomarkers of joint destruction in moderate to severe rheumatoid arthritis

2020 ◽  
Vol 22 (1) ◽  
Author(s):  
Christian S. Thudium ◽  
Anne C. Bay-Jensen ◽  
Suntara Cahya ◽  
Ernst R. Dow ◽  
Morten A. Karsdal ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Clinical Improvement ◽  
Mixed Model ◽  
Activity Index ◽  
Joint Destruction ◽  
Janus Kinase ◽  
Repeated Measure ◽  
Controlled Study ◽  
Joint Tissue

Abstract Background Tissue released blood-based biomarkers can provide insight into drug mode of action and response. To understand the changes in extracellular matrix turnover, we analyzed biomarkers associated with joint tissue turnover from a phase 3, randomized, placebo-controlled study of baricitinib in patients with active rheumatoid arthritis (RA). Methods Serum biomarkers associated with synovial inflammation (C1M, C3M, and C4M), cartilage degradation (C2M), bone resorption (CTX-I), and bone formation (osteocalcin) were analyzed at baseline, and weeks 4 and 12, from a subgroup of patients (n = 240) randomized to placebo or 2-mg or 4-mg baricitinib (RA-BUILD, NCT01721057). Mixed-model repeated measure was used to identify biomarkers altered by baricitinib. The relationship between changes in biomarkers and clinical measures was evaluated using correlation analysis. Results Treatment arms were well balanced for baseline biomarkers, demographics, and disease activity. At week 4, baricitinib 4-mg significantly reduced C1M from baseline by 21% compared to placebo (p < 0.01); suppression was sustained at week 12 (27%, p < 0.001). Baricitinib 4-mg reduced C3M and C4M at week 4 by 14% and 12% compared to placebo, respectively (p < 0.001); they remained reduced by 16% and 11% at week 12 (p < 0.001). In a pooled analysis including all treatment arms, patients with the largest reduction (upper 25% quartile) in C1M, C3M, and C4M by week 12 had significantly greater clinical improvement in the Simplified Disease Activity Index at week 12 compared to patients with the smallest reduction (lowest 25% quartile). Conclusion Baricitinib treatment resulted in reduced circulating biomarkers associated with joint tissue destruction as well as concomitant RA clinical improvement. Trial registration ClinicalTrials.gov NCT01721057; date of registration: November 1, 2012

scholarly journals LXR nuclear receptors prompt a pro-inflammatory gene and functional profile in human macrophages

2021 ◽  
Author(s):  
Arturo González de la Aleja1 ◽  
Mónica Torres-Torresano ◽  
Juan Vladimir de la Rosa ◽  
Barbara Alonso ◽  
Enrique Capa-Sardón ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cell ◽  
Cholesterol Metabolism ◽  
Macrophage Polarization ◽  
Human Monocyte ◽  
Gene Signature ◽  
Human Macrophage ◽  
Human Macrophages ◽  
Inflammatory Gene ◽  
Anti Inflammatory

Abstract Liver X Receptors (LXR) control cholesterol metabolism and exert anti-inflammatory actions in activated macrophages. However, their contribution to human macrophage polarization in the absence of pathogenic stimuli remains unclear. In fact, the LXR pathway has been reported to be significantly enriched in pro-inflammatory synovial macrophages from rheumatoid arthritis patients as well as in immunosuppressive tumors-associated macrophages from human metastatic colon tumors. To determine the role of LXR on macrophage differentiation and polarization, we have analyzed the contribution of LXR to the acquisition of the inflammatory and T-cell-activating functions of human monocyte-derived macrophages. We now report that LXR activation prompts the acquisition of a pro-inflammatory gene signature in human macrophages, whereas LXR inactivation results in enrichment of an anti-inflammatory gene profile. Accordingly, activation and inhibition of LXR oppositely alter the production of cytokines (e.g., TNF, IL1b, CCL17, CCL19, IFNb1) and T cell stimulation activities associated to human macrophage polarization. Mechanistically, the LXR-stimulated macrophage polarization shift relies on their ability to modulate the expression of MAFB and MAF, which govern the acquisition of the macrophage anti-inflammatory profile. The pathological significance of the LXR-mediated macrophage polarization shift was demonstrated by the ability of LXR agonists to modulate macrophage polarization promoted by either tumor-derived ascitic fluids or by synovial fluid from rheumatoid arthritis patients. As a whole, our results demonstrate that LXR activation prompts the acquisition of a pro-inflammatory transcriptional and functional specialization in human macrophages .

scholarly journals Rheumatoid Arthritis, Depression, and the Role of Celecoxib

2020 ◽  
Vol 2 (10) ◽  
pp. 1848-1852
Author(s):  
Nadeen Al-Baz ◽  
Mustafa Abdul Karim
Keyword(s):  
Rheumatoid Arthritis ◽  
Financial Distress ◽  
Clinical Symptoms ◽  
Joint Destruction ◽  
Modest Improvement ◽  
Inflammatory Drugs ◽  
Anti Inflammatory ◽  
Chronic Autoimmune Disease ◽  
Biologic Factors

Abstract Rheumatoid arthritis (RA) is a chronic autoimmune disease, causing joint destruction and associated physical, mental, and financial distress. Depression is not uncommonly found in patients with RA as both disorders share sociodemographic, functional, and biologic factors. There is growing evidence on the role of anti-inflammatory agents in managing depression, particularly celecoxib, which has been shown to significantly alleviate depressive symptoms as an augmenting agent. Compared with traditional nonsteroidal anti-inflammatory drugs (tNSAIDs), however, celecoxib offers modest improvement in clinical symptoms, with uncertain results for pain management, physical function, and adverse effects in patients with RA. Further research is needed to assess the effectiveness of celecoxib in the management of RA, particularly in patients suffering from comorbid depression.

scholarly journals Apoptotic and Anti-Inflammatory Effects of Eupatorium japonicum Thunb. in Rheumatoid Arthritis Fibroblast-Like Synoviocytes

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Jong-Il Shin ◽  
Yong-Joon Jeon ◽  
Sol Lee ◽  
Yoon Gyeong Lee ◽  
Ji Beom Kim ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Natural Product ◽  
Dependent Manner ◽  
Autoimmune Inflammatory Disease ◽  
Treatment Dose ◽  
Natural Product Library ◽  
Anti Inflammatory ◽  
Apoptotic Effects ◽  
Dose Dependent ◽  
Eupatorium Japonicum

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by synovitis, hyperplasia, and the destruction of bone and cartilage. A variety of immunosuppressive biological agents have been developed because the pathogenesis of RA is related predominantly to the inflammatory response. However, rheumatoid arthritis fibroblast-like synovial cells (RAFLS), which are known to play an important role in RA progression, exhibit resistance to immunosuppressants through cancer-like properties. In this study, we identified a novel therapeutic compound for RA, which reduced inflammation and the abnormal proliferation of RAFLS in natural product library made from Korean native plants. Eupatorium japonicum Thunb. (EJT) extract, a component of the natural product library, most effectively reduced viability through the induction of ROS-mediated apoptosis in a dose-dependent manner. In addition, the increased ROS induced the expression of ATF4 and CHOP, key players in ER stress-mediated apoptosis. Interestingly, EJT extract treatment dose-dependently reduced the expression of IL-1β and the transcription of MMP-9, which were induced by TNF-α treatment, through the inhibition of NF-κB and p38 activation. Collectively, we found that EJT extract exerted apoptotic effects through increases in ROS production and CHOP expression and exerted anti-inflammatory effects through the suppression of NF-κB activation, IL-1β expression, and MMP-9 transcription.

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