Lyssia Gruaz
University of Geneva
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Featured researches published by Lyssia Gruaz.
Proceedings of the National Academy of Sciences of the United States of America | 2009
Danielle Burger; Nicolas Molnarfi; Martin S. Weber; Karim J. Brandt; Mahdia Benkhoucha; Lyssia Gruaz; Michel Chofflon; Scott S. Zamvil; Patrice H. Lalive
Mechanisms of action as well as cellular targets of glatiramer acetate (GA) in multiple sclerosis (MS) are still not entirely understood. IL-1β is present in CNS-infiltrating macrophages and microglial cells and is an important mediator of inflammation in experimental autoimmune encephalitis (EAE), the MS animal model. A natural inhibitor of IL-1β, the secreted form of IL-1 receptor antagonist (sIL-1Ra) improves EAE disease course. In this study we examined the effects of GA on the IL-1 system. In vivo, GA treatment enhanced sIL-1Ra blood levels in both EAE mice and patients with MS, whereas IL-1β levels remained undetectable. In vitro, GA per se induced the transcription and production of sIL-1Ra in isolated human monocytes. Furthermore, in T cell contact-activated monocytes, a mechanism relevant to chronic inflammation, GA strongly diminished the expression of IL-1β and enhanced that of sIL-1Ra. This contrasts with the effect of GA in monocytes activated upon acute inflammatory conditions. Indeed, in LPS-activated monocytes, IL-1β and sIL-1Ra production were increased in the presence of GA. These results demonstrate that, in chronic inflammatory conditions, GA enhances circulating sIL-1Ra levels and directly affects monocytes by triggering a bias toward a less inflammatory profile, increasing sIL-1Ra while diminishing IL-1β production. This study sheds light on a mechanism that is likely to participate in the therapeutic effects of GA in MS.
Journal of Leukocyte Biology | 2008
Anna Scanu; Nicolas Molnarfi; Karim J. Brandt; Lyssia Gruaz; Jean-Michel Dayer; Danielle Burger
Imbalance in cytokine homeostasis plays an important part in the pathogenesis of chronic inflammatory diseases such as multiple sclerosis and rheumatoid arthritis. We demonstrated that T cells might exert a pathological effect through direct cellular contact with human monocytes/macrophages, inducing a massive up‐regulation of the prototypical proinflammatory cytokines IL‐1β and TNF. This mechanism that might be implicated in chronic inflammation is specifically inhibited by high‐density lipoproteins (HDL). Like many other stimuli, besides proinflammatory cytokines, the contact‐mediated activation of monocytes induces the production of cytokine inhibitors such as the secreted form of the IL‐1 receptor antagonist (sIL‐1Ra). The present study demonstrates that stimulated T cells generate microparticles (MP) that induce the production of TNF, IL‐1β, and sIL‐1Ra in human monocytes; the production of TNF and IL‐1β but not that of sIL‐1Ra is inhibited in the presence of HDL. The results were similar when monocytes were stimulated by whole membranes of T cells or soluble extracts of the latter. This suggests that MP carry similar monocyte‐activating factors to cells from which they originate. Thus, by releasing MP, T cells might convey surface molecules similar to those involved in the activation of monocytes by cellular contact. By extension, MP might affect the activity of cells, which are usually not in direct contact with T cells at the inflammatory site. Furthermore, this study demonstrates that HDL exert an anti‐inflammatory effect in nonseptic activation of human monocytes, not only by inhibiting the production of IL‐1β and TNF but also, by leaving sIL‐1Ra production unchanged.
Journal of Immunology | 2007
Nicolas Molnarfi; Lyssia Gruaz; Jean-Michel Dayer; Danielle Burger
The unbalanced production of IL-1β and its natural, specific inhibitor, the secreted IL-1R antagonist (sIL-1Ra), plays an important role in chronic/sterile inflammation. Relevant to this condition is direct cellular contact with stimulated T cells which is a potent inducer of cytokine production in human monocytes/macrophages. We previously demonstrated that activation of PI3Ks is a prerequisite of the transcription of the sIL-1Ra gene in human monocytes activated by IFN-β. In this study, we addressed the question of PI3K involvement in the production of IL-1β and sIL-1Ra in monocytes activated by cellular contact with stimulated T cells (mimicked by CHAPS-solubilized membranes of stimulated T cells (CEsHUT)), and a crude preparation of LPS, to compare stimuli relevant to chronic/sterile and acute/infectious inflammation, respectively. In monocytes activated by either CEsHUT or LPS, the inhibition of PI3Ks abrogated sIL-1Ra transcript expression and sIL-1Ra production, demonstrating that PI3Ks control the induction of sIL-1Ra gene transcription. In contrast, PI3K inhibition increased the production of IL-1β protein in both CEsHUT- and LPS-activated monocytes, the enhancement being drastically higher in the former. This was not due to changes in IL-1β mRNA steady-state levels or transcript stability, but to the involvement of PI3Ks in the repression of IL-1β secretion. The downstream PI3K effector, Akt, was implicated in this process. The present results demonstrate that PI3Ks are involved in the inhibition of IL-1β secretion and in the induction of sIL-1Ra production in human blood monocytes by controlling different mechanisms in conditions mimicking chronic/sterile (CEsHUT) and acute/infectious (LPS) inflammation.
Arthritis Research & Therapy | 2010
Anna Scanu; Francesca Oliviero; Lyssia Gruaz; Paolo Sfriso; Assunta Pozzuoli; Federica Frezzato; Carlo Agostini; Danielle Burger; Leonardo Punzi
IntroductionTo investigate whether monosodium urate (MSU) crystals induce the production of CCL2 (monocyte chemoattractant protein-1; MCP-1) in human fibroblast-like synoviocytes (FLS) and whether this mechanism would be affected by high-density lipoproteins (HDL).MethodsHuman FLS isolated from synovial tissue explants were stimulated with MSU crystals (0.01 to 0.5 mg/ml) or interleukin (IL)-1β (10 pg/ml) in the presence or absence of HDL (50 and 100 μg/ml). The production and expression of CCL2 was evaluated with ELISA, confocal microscopy, immunofluorescence microscopy, chemotaxis assay, and real-time quantitative PCR.ResultsExposure of FLS to MSU crystals induced CCL2 accumulation in culture medium in a dose- and time-dependent manner, reaching a plateau at 50 to 75 μg/ml MSU crystals and 20 to 24 hours. Although low, the induced CCL2 levels were sufficient to trigger mononuclear cell migration. In resting FLS, CCL2 was localized in small cytoplasmic vesicles whose number diminished with MSU crystal stimulation. Concomitantly, MSU crystals triggered the induction of CCL2 mRNA expression. All these processes were inhibited by HDL, which cause a 50% decrease in CCL2 mRNA levels and a dose-dependent inhibition of the release of CCL2. Similar results were obtained when FLS were pretreated with HDL and washed before activation by MSU crystals or IL-1β, suggesting a direct effect of HDL on the FLS activation state.ConclusionsThe present results demonstrate that MSU crystals induce FLS to release CCL2 that is stored in vesicles in resting conditions. This mechanism is inhibited by HDL, which may limit the inflammatory process by diminishing CCL2 production and, in turn, monocytes/macrophages recruitment in joints. This study confirms the antiinflammatory functions of HDL, which might play a part in the limitation of acute gout attack.
PLOS ONE | 2010
Rakel Carpintero; Lyssia Gruaz; Karim J. Brandt; Anna Scanu; Dorothée Faille; Valery Combes; Georges E. Grau; Danielle Burger
Background Direct cellular contact with stimulated T cells is a potent mechanism that induces cytokine production in human monocytes in the absence of an infectious agent. This mechanism is likely to be relevant to T cell-mediated inflammatory diseases such as rheumatoid arthritis and multiple sclerosis. Microparticles (MP) generated by stimulated T cells (MPT) display similar monocyte activating ability to whole T cells, isolated T cell membranes, or solubilized T cell membranes. We previously demonstrated that high-density lipoproteins (HDL) inhibited T cell contact- and MPT-induced production of IL-1β but not of its natural inhibitor, the secreted form of IL-1 receptor antagonist (sIL-1Ra). Methodology/Principal Findings Labeled MPT were used to assess their interaction with monocytes and T lymphocytes by flow cytometry. Similarly, interactions of labeled HDL with monocytes and MPT were assessed by flow cytometry. In parallel, the MPT-induction of IL-1β and sIL-1Ra production in human monocytes and the effect of HDL were assessed in cell cultures. The results show that MPT, but not MP generated by activated endothelial cells, bond monocytes to trigger cytokine production. MPT did not bind T cells. The inhibition of IL-1β production by HDL correlated with the inhibition of MPT binding to monocytes. HDL interacted with MPT rather than with monocytes suggesting that they bound the activating factor(s) of T cell surface. Furthermore, prototypical pro-inflammatory cytokines and chemokines such as TNF, IL-6, IL-8, CCL3 and CCL4 displayed a pattern of production induced by MPT and inhibition by HDL similar to IL-1β, whereas the production of CCL2, like that of sIL-1Ra, was not inhibited by HDL. Conclusions/Significance HDL inhibit both MPT binding to monocytes and the MPT-induced production of some but not all cytokines, shedding new light on the mechanism by which HDL display their anti-inflammatory functions.
Journal of Immunology | 2005
Nicolas Molnarfi; Nevila Hyka-Nouspikel; Lyssia Gruaz; Jean-Michel Dayer; Danielle Burger
IFN-β induces the production of secreted IL-1R antagonist (sIL-1Ra) without triggering synthesis of the agonist IL-1β in human monocytes. This might account for its anti-inflammatory properties. Canonically, IFN-β signals through activation of JAK/STAT pathway, although PI3K and MAPK have also been involved. In this study, the role of PI3K, MEK1, and STAT1 in IFN-β-induced sIL-1Ra production is investigated in freshly isolated human blood monocytes. PI3K, but not MEK1 activation is essential for sIL-1Ra production in monocytes treated with IFN-β, as demonstrated by using the respective inhibitors of PI3K and MEK1, Ly294002 and PD98059. The use of cycloheximide and actinomycin D shows that sIL-1Ra was an immediate early gene induced by IFN-β and that PI3K was controlling sIL-1Ra gene transcription. Although both inhibitors of PI3K and MEK1 diminished the Ser727 phosphorylation of STAT1 induced by IFN-β, only Ly294002 inhibited sIL-1Ra production. Furthermore, the inhibition of STAT1-Ser727 phosphorylation by Ly294002 did not affect STAT1 translocation, suggesting that STAT1 was not involved in sIL-1Ra gene induction. This was confirmed in monocytes that were transfected with small interfering RNA specifically targeting STAT1. Indeed, monocytes in which effective STAT1 gene knockdown was achieved were fully responsive to IFN-β in terms of sIL-1Ra production. Taken together, the present data demonstrate that the induction of sIL-1Ra transcription and production by IFN-β in human monocytes involved PI3K, but not STAT1 activation.
Proceedings of the National Academy of Sciences of the United States of America | 2010
Rakel Carpintero; Karim J. Brandt; Lyssia Gruaz; Nicolas Molnarfi; Patrice H. Lalive; Danielle Burger
Glatiramer acetate (GA), an immunomodulator used in multiple sclerosis (MS) therapy, induces the production of secreted IL-1 receptor antagonist (sIL-1Ra), a natural inhibitor of IL-1β, in human monocytes, and in turn enhances sIL-1Ra circulating levels in MS patients. GA is a mixture of peptides with random Glu, Lys, Ala, and Tyr sequences of high polarity and hydrophilic nature that is unlikely to cross the blood–brain barrier. In contrast, sIL-1Ra crosses the blood–brain barrier and, in turn, may mediate GA anti-inflammatory activities within the CNS by counteracting IL-1β activities. Here we identify intracellular signaling pathways induced by GA that control sIL-1Ra expression in human monocytes. By using kinase knockdown and specific inhibitors, we demonstrate that GA induces sIL-1Ra production via the activation of PI3Kδ, Akt, MEK1/2, and ERK1/2, demonstrating that both PI3Kδ/Akt and MEK/ERK pathways rule sIL-1Ra expression in human monocytes. The pathways act in parallel upstream glycogen synthase kinase-3α/β (GSK3α/β), the knockdown of which enhances sIL-1Ra production. Together, our findings demonstrate the existence of signal transduction triggered by GA, further highlighting the mechanisms of action of this drug in MS.
PLOS ONE | 2010
Lyssia Gruaz; Celine Delucinge-Vivier; Patrick Descombes; Jean-Michel Dayer; Danielle Burger
Background Cellular contact with stimulated T cells is a potent inducer of cytokine production in human monocytes and is likely to play a substantial part in chronic/sterile inflammatory diseases. High-density lipoproteins (HDL) specifically inhibit the production of pro-inflammatory cytokines induced by T cell contact. Methodology/Principal Findings To further elucidate the pro-inflammatory functions of cellular contact with stimulated T cells and its inhibition by HDL, we carried out multiplex and microarray analyses. Multiplex analysis of monocyte supernatant revealed that 12 out of 27 cytokines were induced upon contact with stimulated T cells, which cytokines included IL-1Ra, G-CSF, GM-CSF, IFNγ, CCL2, CCL5, TNF, IL-1β, IL-6, IL-8, CCL3, and CCL4, but only the latter six were inhibited by HDL. Microarray analysis showed that 437 out of 54,675 probe sets were enhanced in monocytes activated by contact with stimulated T cells, 164 probe sets (i.e., 38%) being inhibited by HDL. These results were validated by qPCR. Interestingly, the cytokines induced by T cell contact in monocytes comprised IL-1β, IL-6 but not IL-12, suggesting that this mechanism might favor Th17 polarization, which emphasizes the relevance of this mechanism to chronic inflammatory diseases and highlights the contrast with acute inflammatory conditions that usually involve lipopolysaccharides (LPS). In addition, the expression of miR-155 and production of prostaglandin E2—both involved in inflammatory response—were triggered by T cell contact and inhibited in the presence of HDL. Conclusions/Significance These results leave no doubt as to the pro-inflammatory nature of T cell contact-activation of human monocytes and the anti-inflammatory functions of HDL.
Journal of Immunology | 2004
Danielle Burger; Nicolas Molnarfi; Lyssia Gruaz; Jean-Michel Dayer
Cellular contact with stimulated T cells potently induces cytokine production in monocytes, a mechanism that is likely to be relevant to chronic inflammation. Although the identity of surface molecules involved in this process remains elusive, CD40 and its ligand, CD40L, are thought to be implicated, considering that they are expressed at the inflammatory site. To ascertain the involvement of CD40L, we compared the activation of three different types of human monocytic cells, i.e., freshly isolated monocytes, monocytes primed with IFN-γ (IFN-γ-macrophages), and THP-1 cells. These cells were activated by either membranes isolated from stimulated T cells (HUT-78 or T lymphocytes) to mimic cellular contact, soluble extracts from isolated membranes, or CD40L trimer (CD40LT). The production of TNF and IL-1β was induced by membranes of stimulated T cells in the three types of target cells, whereas CD40LT induced TNF production in IFN-γ-macrophages only. Similar results were obtained with soluble extracts of T cell membranes, demonstrating that the difference between membranes and CD40LT was not due to the particulate form of membranes. CD40LT induced neither transcript nor protein of cytokines in monocytes, whereas in IFN-γ-macrophages, IL-1β and TNF mRNA were observed, but only TNF was measured in cell supernatants. Finally, anti-CD40L Abs failed to inhibit TNF and IL-1β production induced in IFN-γ-macrophages by solubilized membranes, whereas TNF production induced by CD40LT was inhibited. These results demonstrate that CD40L is not required in monocyte activation by direct cellular contact with stimulated T cells, although soluble CD40LT induces the production of TNF in IFN-γ-macrophages.
Journal of Neuroimmunology | 2004
Nicolas Molnarfi; Lyssia Gruaz; Jean-Michel Dayer; Danielle Burger
Multiple sclerosis (MS) is an immune-mediated disease improved by interferon-beta (IFNbeta) therapy. IFNbeta may owe its anti-inflammatory property to its ability to induce interleukin-1 receptor antagonist (IL-1Ra) without triggering IL-1beta synthesis in human monocytes. Furthermore, we recently demonstrated that IFNbeta inhibits the production of IL-1beta and tumor necrosis factor-alpha (TNF) in human monocytes activated by cellular contact with stimulated T cells, a mechanism which we suspected of playing an important part in the pathogenesis of chronic inflammatory diseases including MS. Here we compare modulatory effects of IFNbeta on the production of proinflammatory cytokines (IL-1beta, IL-1alpha, TNF, and IL-6) and IL-1Ra in human monocytes stimulated by lipopolysaccharides (LPS) and isolated plasma membranes of stimulated T cells (msHUT), which are likely to reflect monocyte activation in acute and chronic inflammation, respectively. In monocytes activated by either LPS or msHUT, IFNbeta did not modulate the secretion of IL-1alpha and IL-6, but it enhanced the production of IL-1Ra in a dose-dependent manner. However, in monocytes activated by msHUT, the expression of cell-associated and intracellular IL-1alpha was inhibited by IFNbeta, correlating with the inhibition of IL-1alpha transcript. IFNbeta inhibited the expression (mRNA) and production (protein) of IL-1beta and TNF, while enhancing those of IL-1Ra in monocytes activated by msHUT. In contrast, in monocytes activated by LPS, IFNbeta enhanced the expression and production of IL-1beta, TNF, and IL-1Ra, suggesting that it did not display anti-inflammatory properties in these conditions. This study demonstrates that IFNbeta displays opposite effects depending on the type of activation of human monocytes, suggesting that it may affect different pathogenic mechanisms in opposite ways.