References of "Tolle, Fabrice 50003207"
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See detailmiRNAs Regulate Cytokine Secretion Induced by Phosphorylated S100A8/A9 in Neutrophils.
Jung, Nicolas; Schenten, Veronique; Bueb, Jean-Luc UL et al

in International journal of molecular sciences (2019), 20(22),

The release of cytokines by neutrophils constitutes an essential process in the development of inflammation by recruiting and activating additional cells. Neutrophils are also able to secrete a complex of ... [more ▼]

The release of cytokines by neutrophils constitutes an essential process in the development of inflammation by recruiting and activating additional cells. Neutrophils are also able to secrete a complex of S100A8 and S100A9 proteins (S100A8/A9), which can amplify the general inflammatory state of the host and is involved in the pathogenesis of several chronic inflammatory diseases, such as rheumatoid arthritis (RA). S100A8/A9 have received renewed attention due to their susceptibility to several function-altering post-translational modifications. In that context, it has been recently demonstrated that only the phosphorylated form of S100A8/A9 (S100A8/A9-P) is able to induce the secretion of several cytokines in neutrophils. Here, we investigate the mechanism by which this post-translational modification of S100A8/A9 can regulate the extracellular activity of the protein complex and its impact on the inflammatory functions of neutrophils. We found that S100A8/A9-P are present in large amounts in the synovial fluids from RA patients, highlighting the importance of this form of S100A8/A9 complex in the inflammation process. Using miRNA-sequencing on S100A8/A9-P-stimulated differentiated HL-60 cells, we identified a dysregulation of miR-146a-5p and miR-155-5p expression through TRL4 signaling pathways. Our data reveal that overexpression of these miRNAs in neutrophil-like cells reduces S100A8/A9-P-mediated secretion of pro-inflammatory cytokines. [less ▲]

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See detailCalcium signaling and regulation of neutrophil functions: Still a long way to go.
Hann, Justine UL; Bueb, Jean-Luc UL; Tolle, Fabrice UL et al

in Journal of leukocyte biology (2019)

Neutrophils are the most abundant leukocytes in blood and disruption in their functions often results in an increased risk of serious infections and inflammatory autoimmune diseases. Following recent ... [more ▼]

Neutrophils are the most abundant leukocytes in blood and disruption in their functions often results in an increased risk of serious infections and inflammatory autoimmune diseases. Following recent discoveries in their influence over disease progression, a resurgence of interest for neutrophil biology has taken place. The multitude of signaling pathways activated by the engagement of numerous types of receptors, with which neutrophils are endowed, reflects the functional complexity of these cells. It is therefore not surprising that there remains a huge lack in the understanding of molecular mechanisms underlining neutrophil functions. Moreover, studies on neutrophils are undoubtedly limited by the difficulty to efficiently edit the cell's genome. Over the past 30 years, compelling evidence has clearly highlighted that Ca(2+) -signaling is governing the key processes associated with neutrophil functions. The confirmation of the role of an elevation of intracellular Ca(2+) concentration has come from studies on NADPH oxidase activation and phagocytosis. In this review, we give an overview and update of our current knowledge on the role of Ca(2+) mobilization in the regulation of pro-inflammatory functions of neutrophils. In particular, we stress the importance of Ca(2+) in the formation of NETs and cytokine secretion in the light of newest findings. This will allow us to embrace how much further we have to go to understand the complex dynamics of Ca(2+) -dependent mechanisms in order to gain more insights into the role of neutrophils in the pathogenesis of inflammatory diseases. The potential for therapeutics to regulate the neutrophil functions, such as Ca(2+) influx inhibitors to prevent autoimmune and chronic inflammatory diseases, has been discussed in the last part of the review. [less ▲]

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See detailRegulation of neutrophil pro-inflammatory functions sheds new light on the pathogenesis of rheumatoid arthritis.
Jung, N.; Bueb, Jean-Luc UL; Tolle, Fabrice UL et al

in Biochemical pharmacology (2019), 165

For more than two centuries now, rheumatoid arthritis (RA) is under investigation intending to discover successful treatment. Despite decades of scientific advances, RA is still representing a challenge ... [more ▼]

For more than two centuries now, rheumatoid arthritis (RA) is under investigation intending to discover successful treatment. Despite decades of scientific advances, RA is still representing a challenge for contemporary medicine. Current drug therapies allow to improve significantly the quality of life of RA patients; however, they are still insufficient to reverse tissue injury and are often generating side-effects. The difficulty arises from the considerable fluctuation of the clinical course of RA among patients, making the predictive prognosis difficult. More and more studies underline the profound influence of the neutrophil multifaceted functions in the pathogenesis of RA. This renewed interest in the complexity of neutrophil functions in RA offers new exciting opportunities for valuable therapeutic targets as well as for safe and well-tolerated RA treatments. In this review, we aim to update the recent findings on the multiple facets of neutrophils in RA, in particular their impact in promoting the RA-based inflammation through the release of the cytokine-like S100A8/A9 protein complex, as well as the importance of NETosis in the disease progression and development. Furthermore, we delve into the complex question of neutrophil heterogeneity and plasticity and discuss the emerging role of miRNAs and epigenetic markers influencing the inflammatory response of neutrophils in RA and how they could constitute the starting point for novel attractive targets in RA therapy. [less ▲]

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See detailSecretion of the Phosphorylated Form of S100A9 from Neutrophils Is Essential for the Proinflammatory Functions of Extracellular S100A8/A9.
Schenten, Veronique; Plancon, Sebastien; Jung, Nicolas UL et al

in Frontiers in immunology (2018), 9

S100A8 and S100A9 are members of the S100 family of cytoplasmic EF-hand Ca(2+)-binding proteins and are abundantly expressed in the cytosol of neutrophils. In addition to their intracellular roles, S100A8 ... [more ▼]

S100A8 and S100A9 are members of the S100 family of cytoplasmic EF-hand Ca(2+)-binding proteins and are abundantly expressed in the cytosol of neutrophils. In addition to their intracellular roles, S100A8/A9 can be secreted in the extracellular environment and are considered as alarmins able to amplify the inflammatory response. The intracellular activity of S100A8/A9 was shown to be regulated by S100A9 phosphorylation, but the importance of this phosphorylation on the extracellular activity of S100A8/A9 has not yet been extensively studied. Our work focuses on the impact of the phosphorylation state of secreted S100A9 on the proinflammatory function of neutrophils. In a first step, we characterized the secretion of S100A8/A9 in different stimulatory conditions and investigated the phosphorylation state of secreted S100A9. Our results on neutrophil-like differentiated HL-60 (dHL-60) cells and purified human neutrophils showed a time-dependent secretion of S100A8/A9 when induced by phorbol 12-myristoyl 13-acetate and this secreted S100A9 was found in a phosphorylated form. Second, we evaluated the impact of this phosphorylation on proinflammatory cytokine expression and secretion in dHL-60 cells. Time course experiments with purified unphosphorylated or phosphorylated S100A8/A9 were performed and the expression and secretion levels of interleukin (IL)-1alpha, IL-1beta, IL-6, tumor necrosis factor alpha, CCL2, CCL3, CCL4, and CXCL8 were measured by real-time PCR and cytometry bead array, respectively. Our results demonstrate that only the phosphorylated form of the complex induces proinflammatory cytokine expression and secretion. For the first time, we provide evidence that S100A8/PhosphoS100A9 is inducing cytokine secretion through toll-like receptor 4 signaling. [less ▲]

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