The interplay between inflammation and metabolism in rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by extensive synovitis resulting in erosions of articular cartilage and marginal bone that lead to joint destruction. The autoimmune process in RA depends on the activation of immune cells, which use intracellular kinases to respond to external stimuli such as cytokines, immune complexes, and antigens. An intricate cytokine network participates in inflammation and in perpetuation of disease by positive feedback loops promoting systemic disorder. The widespread systemic effects mediated by pro-inflammatory cytokines in RA impact on metabolism and in particular in lymphocyte metabolism. Moreover, RA pathobiology seems to share some common pathways with atherosclerosis, including endothelial dysfunction that is related to underlying chronic inflammation. The extent of the metabolic changes and the types of metabolites seen may be good markers of cytokine-mediated inflammatory processes in RA. Altered metabolic fingerprints may be useful in predicting the development of RA in patients with early arthritis as well as in the evaluation of the treatment response. Evidence supports the role of metabolomic analysis as a novel and nontargeted approach for identifying potential biomarkers and for improving the clinical and therapeutical management of patients with chronic inflammatory diseases. Here, we review the metabolic changes occurring in the pathogenesis of RA as well as the implication of the metabolic features in the treatment response.     

Vasohibin蛋白质家族与肿瘤血管新生

血管新生存在于包括肿瘤在内的多种生理和病理过程中,且受到局部环境中血管生成促进因子和抑制因子的共同调节,这一过程对肿瘤增殖、侵袭、转移能力尤为重要。体内存在着许多内源性血管生成调节因子。最近,vasohibin家族作为一个新的血管新生调节因子进入人们的视线,备受关注。本文就vasohibin家族在肿瘤血管新生过程中的重要角色及其在抗血管生成治疗中的应用做一综述。     

Relationship between total ghrelin and inflammation in hemodialysis patients

In hemodialysis (HD) patients studies have shown that plasma ghrelin is increased and it has been speculated that ghrelin levels might be related to systemic inflammation. The present study attempted to correlate the serum levels of total ghrelin with serum TNF-α and IL-6, and with nutritional status and body composition in HD patients. Forty-seven HD patients from a single dialysis unit (18 women, mean age 55.3 ± 12.2 yr; BMI 24.4 ± 4.2 kg/m²; % body fat 29.4 ± 7.4%) were studied and compared to 21 healthy subjects (12 women, 50.7 ± 15.7 yr and BMI 25.6 ± 4.0 kg/m²; % body fat 30.0 ± 5.7%). Biochemical data, serum total ghrelin, TNF-α and IL-6 levels were measured. The body composition was evaluated by dual energy X-ray absortiometry (DEXA) and energy and protein intake were evaluated. Patients showed elevated plasma ghrelin levels when compared to healthy subjects (1.14 ± 1.0 ng/mL vs 0.58 ± 0.4; p < 0.001). There was a positive correlation between ghrelin levels and TNF-α (r = 0.25; p < 0.04), IL-6 (r = 0.42; p < 0.02), and a negative correlation between TNF-α and protein intake (r = −0.28; p < 0.03), and energy intake (r = −0.34; p < 0.01). No correlation was observed with any aspect of body composition. Plasma ghrelin levels are elevated in HD patients and associated with the state of systemic inflammation. We suggest that the inflammatory state may affect ghrelin bioactivity and metabolism in hemodialysis patients.     

NK4 therapy: a new approach to target angiogenesis and inflammation in rheumatoid arthritis

Rheumatoid arthritis (RA) is a progressive autoimmune disease characterized by synovial membrane hyperplasia, inflammation, and angiogenesis. Hepatocyte growth factor (HGF) and its receptor, c-Met, are both overexpressed in the RA synovium. NK4 is an antagonist of HGF which has been shown to inhibit tumor growth, metastasis, and angiogenesis. In an experimental model of RA, NK4 gene therapy inhibited joint damage and inflammation in both preventative and therapeutic models. NK4 treatment therefore represents a possible therapeutic option in combating RA.Rheumatoid arthritis (RA) is a progressive, inflammatory autoimmune disease characterized by an erosive synovitis. In addition to being an inflammatory condition, RA is also considered to be a member of the angiogenic family of diseases. Angiogenesis is growth of new blood vessels from pre-existing blood vessels. As the disease progresses, the hyperplastic synovial pannus creates a hypoxic, inflammatory environment that induces angiogenesis. Further vascularization of the synovial tissue promotes pannus growth and continued infiltration of inflammatory leukocytes, thus perpetuating the disease.In the previous issue of Arthritis Research & Therapy, Tsunemi and colleagues [1] reported on the targeting of hepatocyte growth factor (HGF) by NK4 in the treatment of RA. HGF is a pleiotropic growth factor that is expressed by mesenchymal cells and promotes processes such as mitogenesis, differentiation, and angiogenesis [2]. It mediates these functions via binding to its unique receptor c-Met, a receptor tyrosine kinase. c-Met is expressed by a variety of cell types, including endothelial cells (ECs) [3].We have previously shown that HGF is elevated in the synovial fluid of patients with RA [4]. More recently, Grandaunet and colleagues [5] found that plasma levels of HGF predict the severity of joint damage in patients with RA. In the joint, we found that HGF and c-Met are elevated in the RA synovial lining compared with normal controls [4]. The report by Tsunemi and colleagues [1] supports these findings and further shows that c-Met is expressed on fibroblasts, mononuclear cells, and ECs in the RA synovium.HGF is a heterodimeric protein composed of an ?-chain, which contains four kringle domains, and a ?-chain [6]. The ?-chain binds c-Met with high affinity, whereas the ?-chain is responsible for activation of c-Met. In an attempt to inhibit HGF, Date and colleagues [7] generated a cleavage product of HGF termed NK4, which contains the four kringle domains of the HGF ?-chain. Therefore, NK4 serves as an antagonist of HGF and can bind c-Met with high affinity without activating it.As described above, one of the primary functions of HGF is to induce angiogenesis by binding to c-Met on the surface of ECs. Therefore, it was postulated that NK4 would act as a competitive inhibitor of HGF, thus inhibiting angiogenesis. Indeed, NK4 has been shown to inhibit angiogenesis in vitro and in various in vivo cancer models [6,8,9]. However, in addition to having antagonistic action against HGF, NK4 inhibits angiogenesis induced by vascular endothelial growth factor and basic fibroblast growth factor in a c-Met-independent fashion [9]. In addition to c-Met, NK4 binds to perlecan, a sulfate proteoglycan that interacts with the vascular endothelial basement membrane. Sakai and colleagues [9] found, specifically, that NK4 binds perlecan and prevents proper fibronectin assembly in the basement membrane, which inhibits several facets of angiogenesis.These features of NK4 make it an attractive potential adjunctive therapy in angiogenic diseases. Over the past decade, numerous studies have been performed to assess the efficacy of either a recombinant NK4 protein or NK4 gene expression vector in many experimental cancer models [3,6]. Collectively, these studies have indicated that NK4 treatment has the potential to inhibit tumor growth, angiogenesis, and metastasis [3,6]. Much of the preclinical success of NK4 can be attributed to its ability to inhibit multiple pathways involved in growth and angiogenesis.RA is driven by inflammation and angiogenesis, and thus much work has been aimed at identifying and testing potential angiogenesis inhibitors in models of experimental arthritis [10]. Tsunemi and colleagues [1] have now adopted their approach of studying the antiangiogenic properties of NK4 in cancer to experimental arthritis. Using an adenovirus vector containing the NK4 gene, they found that NK4 inhibited the development of ?-glucan-induced arthritis [1]. NK4 was able to inhibit inflammation, joint swelling, and bone erosion. However, the authors did not show direct evidence of NK4 inhibiting synovial blood vessel density. Importantly, they also showed that NK4 gene therapy was effective when given therapeutically, after the onset of the experimental arthritis [1].These results are highly encouraging in the application of NK4 as a potential adjunctive RA therapy. This report, coupled with the high expression levels of HGF and c-Met in the RA synovium, makes NK4 treatment an intriguing possibility. In the future, it will be of great interest to determine whether these effects of NK4 are observable in other animal models of RA, as not all facets of RA are represented in a singular model of the disease. Moreover, many of the effects of NK4 observed by Tsunemi and colleagues [1] are attributed to a reduction in inflammation and inflammatory cytokines. Therefore, elucidating the anti-inflammatory and antiangiogenic mechanisms of NK4 will be paramount to transitioning from an interesting candidate to a possible RA therapy.     

Keratan sulfate suppresses cartilage damage and ameliorates inflammation in an experimental mice arthritis model

Proteoglycans bearing keratan sulfate (KS), such as aggrecan, are components of the human cartilage extracellular matrix (ECM). However, the role of KS in influencing cartilage degradation associated with arthritis remains to be completely understood. KS side chains of the length found in human cartilage are not found in murine skeletal tissues. Using a murine model of inflammatory polyarthritis and cartilage explants exposed to interleukin-1α (IL-1α), we examined whether administering KS could influence intraarticular inflammation and cartilage degradation. Acute arthritis was induced by intravenous administration of an anti-type II collagen antibody cocktail, followed by an intraperitoneal injection of lipopolysaccharide. This treatment was followed by an intraperitoneal KS administration in half of the total mice to evaluate the therapeutic potential of KS for ameliorating arthritis. To investigate the therapeutic potential ex vivo, we examined cartilage fragility by measuring IL-1α-induced aggrecan release from cartilage explants treated with or without KS. Intraperitoneal KS administration ameliorated arthritis in DBA/1J mice. The aggrecan release induced by IL-1α was less in cartilage explants containing media with KS than in those without KS. Our data indicate that exogenous KS ameliorated arthritis in vivo and suppressed cartilage degradation ex vivo. KS may have important therapeutic potential in the treatment of inflammatory arthritis. The mechanism responsible for this requires further investigation, but KS may become a novel therapeutic agent for treating inflammatory diseases such as rheumatoid arthritis.     

The neuroimmune semaphorin-3A reduces inflammation and progression of experimental autoimmune arthritis

Semaphorin-3A (Sema3A), a member of a large family of conserved proteins originally implicated in axon guidance, is expressed by activated T cells and downmodulates T cell activation in vitro. This study examined the effect and mechanism of action of Sema3A overexpression in a mouse model of collagen-induced arthritis. Prophylactic i.p. administration of plasmid DNA encoding Sema3A markedly reduced the incidence, disease severity, and articular inflammation compared with control plasmid without insert. Treatment of Sema3A reduced anticollagen IgG levels and suppressed collagen-specific proinflammatory cytokine (IFN-γ and IL-17) release, but increased IL-10 concentration in the serum. In line with results in arthritic mice, Sema3A expression is defective in CD4(+) T cells derived from patients with rheumatoid arthritis. In contrast, increased expression of the Sema3A receptor neuropilin-1 (NP-1) is detected in the same cells. The CD4(+)NP-1(+) T cells are a T cell subset involved in the control of the immune responses. They express greater amounts of IL-10 and show suppressive activities on autologous CD4(+) T cells. Sema3A acted directly on CD4(+)NP-1(+) T cells, because it could increase IL-10 production and influence the regulatory function on CD4(+) T cell growth. Therefore, I propose that Sema3A increases the CD4(+)NP-1(+) T cell ability to suppress alloresponses, that its transient expression is altered in rheumatoid inflammation, and that reintroduction of Sema3A is sufficient to attenuate collagen-induced arthritis, supporting its therapeutic potential in the treatment of autoimmune disorders.     

Relationship between vasculogenesis, angiogenesis and haemopoiesis during avian ontogeny

Quail-chick intracoelomic grafts of organ rudiments were used to study the origin of endothelia and haemopoietic cells during avian organogenesis in conjunction with the monoclonal antibody QH1 which recognizes the quail haemangioblastic lineage. Results differed according to the germ-layer constitution of the grafted rudiments. In the case of the limb buds, endothelial cells from the host invaded the graft through an angiogenic process. Haemopoietic progenitors from the host also colonized the grafted bone marrow. In contrast, rudiments of internal organs provided their own contingent of endothelial precursors, a process termed vasculogenesis. Nevertheless, haemopoietic cells in these organs were all derived from the host. In the lung, this extrinsic cell population appeared regularly scattered around the parabronchi and had a macrophage-like phenotype. In the pancreas, the granulocytes which differentiate as dense aggregates located in the wall of the largest vessels were extrinsic. Similarly in the spleen, a mesodermal primordium that develops in close association with the pancreatic endoderm, endothelial cells were intrinsic and haemopoietic cells host-derived. This study demonstrates that, in ontogeny, vascularization obeys different rules depending on which germ layer the mesoderm is associated with: in mesodermal/ectodermal rudiments angiogenesis is the rule; in mesodermal/endodermal rudiments, vasculogenesis occurs. However, in these internal organs undergoing vasculogenesis, endothelial and haemopoietic cells have separate origins. We put forward the hypothesis that the endoderm induces the emergence of endothelial cells in the associated mesoderm. Formation of blood stem cells may also involve interactions between endoderm and mesoderm, but in this case the responding capacity of the mesoderm appears restricted to the paraaortic region.     

SARI prevents ocular angiogenesis and inflammation in mice

SARI (Suppressor of AP-1, regulated by IFN-β) is known to play an important role in some systemic disease processes such an inflammatory conditions and cancer. We hypothesize that SARI may also play a role in ocular diseases involving inflammation and neovascularization. To explore our hypothesis, further, we investigated an endotoxin-induced uveitis (EIU) and experimental argon laser-induced choroidal neovascularization (CNV) model in SARI wild-type (SARI^WT) and SARI-deficient (SARI^−/−) mice. Through imaging, morphological and immunohistochemical (IHC) studies, we found that SARI deficiency exacerbated the growth of CNV. More VEGF-positive cells were presented in the retina of SARI^−/− mice with CNV. Compared to SARI^WT mice, more inflammatory cells infiltrated the ocular anterior segment and posterior segments in SARI^−/− mice with EIU. Collectively, the results point to a potential dual functional role of SARI in inflammatory ocular diseases, suggesting that SARI could be a potential therapy target for ocular inflammation and neovascularization.     

Hyaluronan reduces inflammation in experimental arthritis by modulating TLR-2 and TLR-4 cartilage expression

Previous studies have reported that low molecular mass HA and highly polymerized HA respectively elicited pro- and anti-inflammatory responses by modulating the toll-like receptor 4 (TLR-4) and the TLR-2. The activation of TLR-4 and TLR-2 mediated by collagen-induced arthritis (CIA) induces the myeloid differentiation primary response protein (MyD88) and the tumor necrosis factor receptor-associated factor 6 (TRAF6), and ends with the liberation of NF-kB which, in turn, stimulates pro-inflammatory cytokine production. The aim of this study was to investigate the influence of high molecular weight HA at different concentrations on TLR-4 and TLR-2 modulation in CIA in mice. Arthritis was induced in mice via intradermal injection of an emulsion containing bovine type II collagen in complete Freund's adjuvant. Mice were treated with HA intraperitoneally daily for 30 days. CIA increased TLR-4, TLR-2, MyD88 and TRAF6 mRNA expression and the related protein in the cartilage of arthritic joints. High levels of both mRNA and related protein were also detected for tumor necrosis factor alpha (TNF-α), interleukin 1-beta (IL-1-β), interleukin-17 (IL-17), matrix metalloprotease-13 (MMP-13) and inducible nitric oxide synthase (iNOS) in the joint of arthritic mice. HA treatment significantly limited CIA incidence and decreased all the parameters up-regulated by CIA. The improvement of biochemical parameters was also supported by histological analysis, plasma and synovial fluid HA levels. These results suggest that the TLR-4 and TLR-2 play an important role in the arthritis mechanism and the interaction/block of HA at high molecular mass may reduce inflammation and cartilage injury.     

Dendritic cells provide a potential link between smoking and inflammation in rheumatoid arthritis

Introduction

Smoking increases the risk of developing rheumatoid arthritis (RA) and affects the severity of established RA. Smoking can impact on Th17 lymphocyte differentiation and function through activation of the aryl hydrocarbon receptor (AHR), a process with implications for the pathogenic mechanisms in RA that involve the cytokine, interleukin (IL)-17A. The objective of this study was to establish any effect of smoking on the inflammatory tissue lesions of rheumatoid arthritis via the AHR and IL-17A.

Methods

Twenty synovial and eighteen subcutaneous nodule tissue samples from 31 patients with RA were studied. Patient smoking status at the time of tissue collection was established. Expression of AHR, CYP1A1, AHRR, IL6, IL17A, IL17F, IL22, IL23, IL23R, IFNG, TBX21, IDO1 and FOXP3 genes were assessed in tissues and cultured cells using real-time PCR. Two-colour immunofluorescence was used to co-localise AHR and CYP1A1 protein in synovial tissues. The response of monocytes and monocyte-derived dendritic cells (mo-DCs) to the AHR agonist, benzo(a)pyrene (BaP) was compared in vitro.

Results

AHR gene expression was demonstrated in rheumatoid synovial tissues and nodules with significantly greater expression in synovia. Expression was not influenced by smoking in either tissue. Evidence of AHR activation, indicated by CYP1A1 and AHRR gene expression, was found only in synovia from patients who smoked. However, IL17A gene expression was lower in synovia from smokers. TBX21 and FOXP3 expression was not affected by smoking. Within the synovial tissues of smokers the principal cell type with evidence of AHR activation was a subset of synovial DCs. This observation was consistent with the sensitivity of human mo-DCs to BaP stimulation demonstrated in vitro. Exposure to BaP affected mo-DC function as demonstrated by decreased IL6 expression induced by PolyI:C, without affecting indoleamine 2,3 dioxygenase (IDO)1 expression.

Conclusion

Our findings show that one effect of smoking on inflamed rheumatoid synovial tissue involves activation of the AHR pathway. A subset of synovial DCs is important in the response to cigarette smoke. The potential for smoking to affect DC behaviour in joint tissues has relevance to both early and late phases of RA pathogenesis and warrants further investigation.     

Association between autophagy and inflammation in patients with rheumatoid arthritis receiving biologic therapy

Background

Increasing evidence indicates a pathogenic role of deregulated autophagy in rheumatoid arthritis (RA). We examined the relationship between autophagy and inflammatory parameters in patients with RA receiving biologic therapy.

Methods

In 72 patients with RA and 20 healthy control subjects (HC), autophagosome levels were determined by the mean fluorescence intensity (MFI) of autophagosomotropic dye incorporated into circulating immune cells, and p62 expression levels in immune cells were measured by flow cytometry. We used immunoblotting to examine protein expression of LC3-II and p62 in peripheral blood mononuclear cells.

Results

Patients with RA had significantly higher levels of autophagosome reflected by MFI of Cyto-ID in circulating lymphocytes, monocytes, and granulocytes (median values, 3.6, 11.6, and 64.8, respectively) compared with HC (1.9, 6.0, and 35.8; respectively) (all p?<?0.001). p62 MFI levels in lymphocytes and granulocytes from patients with RA (17.1 and 8.6, respectively) were significantly lower than those in the corresponding cells from HC (20.2, p?<?0.05; and 13.1, p?<?0.001, respectively). Significantly higher levels of LC3-II protein expression in contrast to lower p62 protein levels were observed in patients with RA than in HC. The autophagosome levels in immune cells were significantly correlated with inflammatory parameters in patients with RA, and they were significantly decreased with disease remission after treatment with tumor necrosis factor-α inhibitors or interleukin-6 receptor inhibitor.

Conclusions

Elevated autophagy with significant correlation to inflammation suggests the involvement of autophagy in RA pathogenesis. The effectiveness of biologic therapy might be partly related to the downregulation of autophagy expression.

     

Amelioration of inflammation, angiogenesis and CTGF expression in an arthritis model by a TSP1-derived peptide treatment

OBJECTIVE: To evaluate the effect of a thrombospondin 1 (TSP1)-derived peptide on inflammation and angiogenesis in an animal model of erosive arthritis and to assess the relationship between TSP1 and connective tissue growth factor (CTGF) in the pathophysiology of rheumatoid arthritis. METHODS: Erosive arthritis in Lewis rats was induced by peptidoglycan-polysaccharide (PG-PS). Animals were divided into four groups: (1) negative control and groups receiving, (2) no treatment, (3) treatment with a TSP1-derived peptide, and (4) treatment with a scrambled peptide. Samples obtained from ankle joint, spleen and liver were studied using histology, histomorphometry, immunohistochemistry and RT-PCR. RESULTS: Histological data indicated that the TSP1-derived peptide treatment decreased neovascularization, leukocyte infiltration and thickening of the synovial lining of the joint, and reduced granuloma formation in the spleen and liver when compared to control groups. Higher concentrations of CTGF and TSP1 proteins were observed in the affected areas of animals which did not receive TSP1-derived peptide treatment. Also, immunofluorescence and RT-PCR analyses showed an increase in CTGF protein expression and regulation, respectively, in the tissues of untreated animals when compared to the TSP1-derived peptide treated animals. By immunofluorescence, TSP1 expression was decreased in the TSP1-derived peptide treated animals. Moreover, macrophage/monocyte-specific staining revealed a decrease in cell infiltration in the articular tissue of the TSP1-derived peptide treated animals. CONCLUSION: Both inflammation and angiogenesis were decreased after TSP1-derived peptide treatment indicating a potential pathway by which TSP1 interaction with neutrophils induces CTGF in RA affected tissues.     

Differential effects of locally and systemically administered soluble glycoprotein 130 on pain and inflammation in experimental arthritis

Introduction  

Interleukin-6 (IL-6) is a key player in systemic arthritis, involved in inflammation and joint destruction. IL-6 signalling has also been revealed in nerve cells. Recently, IL-6 and in particular IL-6 together with its soluble IL-6 receptor (sIL-6R) were shown to induce a long-lasting robust sensitization of joint nociceptors for mechanical stimuli which was difficult to reverse, suggesting that IL-6 signalling plays a significant role in the generation and maintenance of arthritic pain. Here we tested in a preclinical model of arthritis, antigen-induced arthritis (AIA) in the rat, whether systemic or local neutralization of IL-6/sIL-6R complexes with soluble glycoprotein 130 (sgp130) alters arthritic pain and how sgp130 influences the inflammatory process in AIA.     

Relationship between macrophages in mouse uteri and angiogenesis in endometrium during the peri-implantation period

The objective of this study is to examine the change in macrophage numbers, inducible form of NO synthase (iNOS), and vascular endothelial growth factor (VEGF) expression both before and after embryo implantation in the uterine tissue of mice. In order to explore the mechanism of macrophages in endometrial angiogenesis, 8-week-old female mice were divided into three groups: pregnant group, pseudopregnant group (mated to male mice that had been vasectomized), and estrous group (unmated). Individuals from these three groups were sacrificed at time intervals D1.5 to D6.5. Formalin-fixed paraffin-embedded tissue was used for immunocytochemical localization of Mφ, iNOS, and VEGF utilizing standard methodology. The proportion of macrophages in the peripheral blood was determined by flow cytometry, and the relationship between macrophage, iNOS, and VEGF expression was analyzed. The proportion of peripheral blood macrophages in the pregnancy group was significantly higher than that in the other groups. The results of immunohistochemistry determined that the macrophages exhibited changes in both numbers and distribution. The number of macrophages in the endometrium of the pregnancy and pseudopregnancy groups was significantly higher than that in the control (estrous) group. In the pregnancy group, macrophage numbers dramatically decreased and gradually transferred to the perimetrium on D4.5. Immunostaining revealed strong staining in the pregnancy group and weaker staining in the pseudopregnant and control groups for both iNOS and VEGF. There was strong, dense immunostaining at the implantation site for both iNOS and VEGF, whereas light immunostaining was seen in interimplantation tissues on D5.5 to D6.5. In the pregnant group, peripheral blood and uterine macrophage proportions were negatively correlated, whereas the amount of macrophages, iNOS, and VEGF expression in the endometrium were positively correlated. The expression of iNOS and VEGF in the endometrium also displayed a strong positive correlation. In conclusion, during embryo implantation, macrophages levels decreased in the uterus, whereas the number of peripheral macrophages increased, suggesting that macrophages may migrate into the peripheral blood and uterus to adapt for pregnancy. Additionally, an increase in the expression of iNOS and VEGF was observed during the implantation window, implying that iNOS and VEGF may play an important role in promoting embryo implantation. The positive correlation between macrophages, iNOS, and VEGF in the implanting uterus implied that macrophages might regulate iNOS and VEGF during the implantation process.     

Relationship between obesity, inflammation and insulin resistance: new concepts

White adipose tissue is the main site of energy storage, but it is now recognized as an active participant in regulating physiologic and pathologic processes including immunity and inflammation. It has an endocrine function by secreting at least two main hormones, leptin and adiponectin. It can secrete other products, named adipokines, including cytokines and chemokines, involved in inflammation process. The release of adipokines by either adipocytes or adipose tissue infiltrated macrophages lead to a chronic sub-inflammatory state that could play a central role in cardiovascular complications linked to obesity and insulin resistance, a risk factor to develop type-2 diabetes.     

IL-6-dependent PGE2 secretion by mesenchymal stem cells inhibits local inflammation in experimental arthritis

Background

Based on their capacity to suppress immune responses, multipotent mesenchymal stromal cells (MSC) are intensively studied for various clinical applications. Although it has been shown in vitro that the immunomodulatory effect of MSCs mainly occurs through the secretion of soluble mediators, the mechanism is still not completely understood. The aim of the present study was to better understand the mechanisms underlying the suppressive effect of MSCs in vivo, using cells isolated from mice deficient in the production of inducible nitric oxide synthase (iNOS) or interleukin (IL)-6 in the murine model of collagen-induced arthritis.

Principal Findings

In the present study, we show that primary murine MSCs from various strains of mice or isolated from mice deficient for iNOS or IL-6 exhibit different immunosuppressive potential. The immunomodulatory function of MSCs was mainly attributed to IL-6-dependent secretion of prostaglandin E2 (PGE2) with a minor role for NO. To address the role of these molecules in vivo, we used the collagen-induced arthritis as an experimental model of immune-mediated disorder. MSCs effectively inhibited collagen-induced inflammation during a narrow therapeutic window. In contrast to wild type MSCs, IL-6-deficient MSCs and to a lesser extent iNOS-deficient MSCs were not able to reduce the clinical signs of arthritis. Finally, we show that, independently of NO or IL-6 secretion or Treg cell induction, MSCs modulate the host response by inducing a switch to a Th2 immune response.

Significance

Our data indicate that MSCs mediate their immunosuppressive effect via two modes of action: locally, they reduce inflammation through the secretion of anti-proliferative mediators, such as NO and mainly PGE2, and systemically they switch the host response from a Th1/Th17 towards a Th2 immune profile.     

Soluble Fas ligand inhibits angiogenesis in rheumatoid arthritis

The characteristics of rheumatoid arthritis (RA) pathology include the infiltration of inflammatory leukocytes, the proliferation of synovial cells, and the presence of extensive angiogenesis, referred to as rheumatoid pannus. Fas ligand is critical to the homeostatic regulation of the immune response, but its role in the angiogenic process of RA remains to be defined. In this study, we investigated whether soluble Fas ligand (sFasL) induces synoviocyte apoptosis and regulates angiogenesis of endothelial cells in RA. The levels of sFasL were elevated in the synovial fluids of RA patients when compared to those of osteoarthritis (OA) patients, and they correlated inversely with vascular endothelial growth factor₁₆₅ (VEGF₁₆₅) concentrations. sFasL, ranging from 10 to 100 ng/ml, induced the apoptosis of RA fibroblast-like synoviocytes (FLS) in vitro, and thereby decreased VEGF₁₆₅ production. In addition, sFasL inhibited VEGF₁₆₅-induced migration and chemotaxis of endothelial cells to basal levels in a manner independent of the Fas-mediated cell death. sFasL dose-dependently suppressed the VEGF₁₆₅-stimulated increase in pAkt expression in endothelial cells, which might be associated with its anti-migratory effect on endothelial cells. Moreover, sFasL strongly inhibited neovascularization in the Matrigel plug in vivo. Our data suggest that sFasL shows anti-angiogenic activity within RA joints not only by inducing apoptosis of VEGF₁₆₅-producing cells but also by blocking VEGF₁₆₅-induced migration of endothelial cells, independent of Fas-mediated apoptosis.     

No association between genetic variants in angiogenesis and inflammation pathway genes and breast cancer survival among Chinese women

Background: Angiogenesis and inflammation are implicated in breast cancer prognosis; however, the role of individual germline variation in related genes is unknown. Methods: A two-stage candidate pathway association study was conducted among 6983 Chinese women. Stage 1 included 2884 women followed for a median of 5.7 years; Stage 2 included 4099 women followed for a median of 4.0 years. Cox proportional hazards regression was used to estimate the effects of genetic variants on disease-free survival (DFS) and overall survival (OS). Results: Stage 1 included genotyping of 506 variants in 22 genes; analysis was conducted for 370 common variants. Nominally significant associations with DFS and/or OS were found for 20 loci in ten genes in Stage 1; variants in 19 loci were successfully genotyped and evaluated in Stage 2. In analyses of both study stages combined, nominally significant associations were found for nine variants in seven genes; none of these associations surpassed a significance threshold level corrected for the total number of variants evaluated in this study. Conclusions: No association with survival was found for 370 common variants in 22 angiogenesis and inflammation pathway genes among Chinese women with breast cancer. Impact: Our data do not support a large role for common genetic variation in 22 genes in breast cancer prognosis; research on angiogenesis and inflammation genes should focus on common variation in other genes, rare host variants, or tumor alterations.