Publications by authors named "Samuel Garcia"

76 Publications

Semaphorin3B plays a central role in serum-induced arthritis model and is reduced in patients with rheumatoid arthritis.

Arthritis Rheumatol 2022 Jan 9. Epub 2022 Jan 9.

Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands.

Objectives: Sema(phorin)3B decreases the migrative and invasive capacities of rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) and suppress expression of matrix-metalloproteinases (MMPs). Here, we determined the role of Sema3B in an arthritis mouse model and its expression in RA patients.

Methods: Clinical responses, histological analysis and FLS function were examined in wild-type (WT) and Sema3B-deficient (Sema3b ) mice in the K/BxN serum transfer model of arthritis. Protein and mRNA expression from mice joints and murine FLS, as well as from serum and synovial tissue of arthralgia and RA patients, was determined by ELISA, immunoblotting, qPCR and RNA sequencing. FLS migration was determined using the wound closure assay.

Results: The clinical severity of serum-induced arthritis was significantly higher in Sema3b mice compared to WT mice. This was associated with an increased expression of inflammatory mediators and migratory capacity of mFLS. The administration of recombinant mouse Sema3B reduced the clinical severity of serum-induced arthritis and the expression of inflammatory mediators. Sema3B expression was significantly lower in the synovial tissue and serum of established RA patients compared to arthralgia patients. Sema3B serum levels were elevated in arthralgia patients that later-on progressed to RA, but not in those that did not develop RA; however these levels drastically decreased 1 and 2 years after RA development.

Conclusions: Sema3B expression has a protective role in a mouse model of arthritis. In RA patients, expression levels depend on the disease stage, suggesting different regulatory roles in disease onset and progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/art.42065DOI Listing
January 2022

CXCL4 drives fibrosis by promoting several key cellular and molecular processes.

Cell Rep 2022 01;38(1):110189

Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. Electronic address:

Fibrosis is a major cause of mortality worldwide, characterized by myofibroblast activation and excessive extracellular matrix deposition. Systemic sclerosis is a prototypic fibrotic disease in which CXCL4 is increased and strongly correlates with skin and lung fibrosis. Here we aim to elucidate the role of CXCL4 in fibrosis development. CXCL4 levels are increased in multiple inflammatory and fibrotic mouse models, and, using CXCL4-deficient mice, we demonstrate the essential role of CXCL4 in promoting fibrotic events in the skin, lungs, and heart. Overexpressing human CXCL4 in mice aggravates, whereas blocking CXCL4 reduces, bleomycin-induced fibrosis. Single-cell ligand-receptor analysis predicts CXCL4 to affect endothelial cells and fibroblasts. In vitro, we confirm that CXCL4 directly induces myofibroblast differentiation and collagen synthesis in different precursor cells, including endothelial cells, by stimulating endothelial-to-mesenchymal transition. Our findings identify a pivotal role of CXCL4 in fibrosis, further substantiating the potential role of neutralizing CXCL4 as a therapeutic strategy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2021.110189DOI Listing
January 2022

Distinctive CD26 Expression on CD4 T-Cell Subsets.

Biomolecules 2021 10 2;11(10). Epub 2021 Oct 2.

Rheumatology & Immune-Mediated Diseases Research Group (IRIDIS), Galicia Sur Health Research Institute (IISGS), SERGAS-UVIGO, 36312 Vigo, Spain.

Immune system CD4 T-cells with high cell-surface CD26 expression show anti-tumoral properties. When engineered with a chimeric antigen receptor (CAR), they incite strong responses against solid cancers. This subset was originally associated to human CD4 T helper cells bearing the CD45R0 effector/memory phenotype and later to Th17 cells. CD26 is also found in soluble form (sCD26) in several biological fluids, and its serum levels correlate with specific T cell subsets. However, the relationship between glycoprotein sCD26 and its dipeptidyl peptidase 4 (DPP4) enzymatic activity, and cell-surface CD26 expression is not well understood. We have studied ex vivo cell-surface CD26 and in vitro surface and intracellular CD26 expression and secretome's sCD26 in cultured CD4 T cells under different polarization conditions. We show that most human CD26negative CD4 T cells in circulating lymphocytes are central memory (T) cells while CD26high expression is present in effector Th1, Th2, Th17, and T (effector memory) cells. However, there are significant percentages of Th1, Th2, Th17, and Th22 CD26 negative cells. This information may help to refine the research on CAR-Ts. The cell surface CD45R0 and CD26 levels in the different T helper subsets after in vitro polarization resemble those found ex vivo. In the secretomes of these cultures there was a significant amount of sCD26. However, in all polarizations, including Th1, the levels of sCD26 were lower (although not significantly) compared to the Th0 condition (activation without polarization). These differences could have an impact on the various physiological functions proposed for sCD26/DPP4.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biom11101446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533622PMC
October 2021

Mortality risk attributable to wildfire-related PM pollution: a global time series study in 749 locations.

Lancet Planet Health 2021 09;5(9):e579-e587

Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.

Background: Many regions of the world are now facing more frequent and unprecedentedly large wildfires. However, the association between wildfire-related PM and mortality has not been well characterised. We aimed to comprehensively assess the association between short-term exposure to wildfire-related PM and mortality across various regions of the world.

Methods: For this time series study, data on daily counts of deaths for all causes, cardiovascular causes, and respiratory causes were collected from 749 cities in 43 countries and regions during 2000-16. Daily concentrations of wildfire-related PM were estimated using the three-dimensional chemical transport model GEOS-Chem at a 0·25° × 0·25° resolution. The association between wildfire-related PM exposure and mortality was examined using a quasi-Poisson time series model in each city considering both the current-day and lag effects, and the effect estimates were then pooled using a random-effects meta-analysis. Based on these pooled effect estimates, the population attributable fraction and relative risk (RR) of annual mortality due to acute wildfire-related PM exposure was calculated.

Findings: 65·6 million all-cause deaths, 15·1 million cardiovascular deaths, and 6·8 million respiratory deaths were included in our analyses. The pooled RRs of mortality associated with each 10 μg/m increase in the 3-day moving average (lag 0-2 days) of wildfire-related PM exposure were 1·019 (95% CI 1·016-1·022) for all-cause mortality, 1·017 (1·012-1·021) for cardiovascular mortality, and 1·019 (1·013-1·025) for respiratory mortality. Overall, 0·62% (95% CI 0·48-0·75) of all-cause deaths, 0·55% (0·43-0·67) of cardiovascular deaths, and 0·64% (0·50-0·78) of respiratory deaths were annually attributable to the acute impacts of wildfire-related PM exposure during the study period.

Interpretation: Short-term exposure to wildfire-related PM was associated with increased risk of mortality. Urgent action is needed to reduce health risks from the increasing wildfires.

Funding: Australian Research Council, Australian National Health & Medical Research Council.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2542-5196(21)00200-XDOI Listing
September 2021

The deep and slow breathing characterizing rest favors brain respiratory-drive.

Sci Rep 2021 03 29;11(1):7044. Epub 2021 Mar 29.

Lyon Neuroscience Research Center (CRNL), Inserm U 1028, CNRS UMR 5292, University Lyon 1, 69675, Bron, France.

A respiration-locked activity in the olfactory brain, mainly originating in the mechano-sensitivity of olfactory sensory neurons to air pressure, propagates from the olfactory bulb to the rest of the brain. Interestingly, changes in nasal airflow rate result in reorganization of olfactory bulb response. By leveraging spontaneous variations of respiratory dynamics during natural conditions, we investigated whether respiratory drive also varies with nasal airflow movements. We analyzed local field potential activity relative to respiratory signal in various brain regions during waking and sleep states. We found that respiration regime was state-specific, and that quiet waking was the only vigilance state during which all the recorded structures can be respiration-driven whatever the respiratory frequency. Using CO-enriched air to alter respiratory regime associated to each state and a respiratory cycle based analysis, we evidenced that the large and strong brain drive observed during quiet waking was related to an optimal trade-off between depth and duration of inspiration in the respiratory pattern, characterizing this specific state. These results show for the first time that changes in respiration regime affect cortical dynamics and that the respiratory regime associated with rest is optimal for respiration to drive the brain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-86525-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007577PMC
March 2021

Calcineurin and Systemic Lupus Erythematosus: The Rationale for Using Calcineurin Inhibitors in the Treatment of Lupus Nephritis.

Int J Mol Sci 2021 Jan 27;22(3). Epub 2021 Jan 27.

Rheumatology & Immuno-mediated Diseases Research Group (IRIDIS), Galicia Sur Health Research Institute (IIS Galicia Sur). SERGAS-UVIGO, 36201 Vigo, Spain.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a broad spectrum of clinical presentations that can affect almost all organ systems. Lupus nephritis (LN) is a severe complication that affects approximately half of the systemic erythematosus lupus (SLE) patients, which significantly increases the morbidity and the mortality risk. LN is characterized by the accumulation of immune complexes, ultimately leading to renal failure. Aberrant activation of T cells plays a critical role in the pathogenesis of both SLE and LN and is involved in the production of inflammatory cytokines, the recruitment of inflammatory cells to the affected tissues and the co-stimulation of B cells. Calcineurin is a serine-threonine phosphatase that, as a consequence of the T cell hyperactivation, induces the production of inflammatory mediators. Moreover, calcineurin is also involved in the alterations of the podocyte phenotype, which contribute to proteinuria and kidney damage observed in LN patients. Therefore, calcineurin inhibitors have been postulated as a potential treatment strategy in LN, since they reduce T cell activation and promote podocyte cytoskeleton stabilization, both being key aspects in the development of LN. Here, we review the role of calcineurin in SLE and the latest findings about calcineurin inhibitors and their mechanisms of action in the treatment of LN.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22031263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865978PMC
January 2021

Angiopoietin-2 Promotes Inflammatory Activation in Monocytes of Systemic Sclerosis Patients.

Int J Mol Sci 2020 Dec 15;21(24). Epub 2020 Dec 15.

Center for Translational Immunology, University Medical Center Utrecht, University of Utrecht, 3508 GA Utrecht, The Netherlands.

Angiopoietin-2 (Ang-2), a ligand of the tyrosine kinase receptor Tie2, is essential for vascular development and blood vessel stability and is also involved in monocyte activation. Here, we examined the role of Ang-2 on monocyte activation in patients with systemic sclerosis (SSc). Ang-2 levels were measured in serum and skin of healthy controls (HCs) and SSc patients by ELISA and array profiling, respectively. mRNA expression of was analyzed in monocytes, dermal fibroblasts, and human pulmonary arterial endothelial cells (HPAECs) by quantitative PCR. Monocytes were stimulated with Ang-2, or with serum from SSc patients in the presence of a Tie2 inhibitor or an anti-Ang2 neutralizing antibody. Interleukin (IL)-6 and IL-8 production was analyzed by ELISA. Ang-2 levels were elevated in the serum and skin of SSc patients compared to HCs. Importantly, serum Ang-2 levels correlated with clinical disease parameters, such as skin involvement. Lipopolysaccharide (LPS) LPS, R848, and interferon alpha2a (IFN-α) stimulation up-regulated the mRNA expression of in monocytes, dermal fibroblasts, and HPAECs. Finally, Ang-2 induced the production of IL-6 and IL-8 in monocytes of SSc patients, while the inhibition of Tie2 or the neutralization of Ang-2 reduced the production of both cytokines in HC monocytes stimulated with the serum of SSc patients. Therefore, Ang-2 induces inflammatory activation of SSc monocytes and neutralization of Ang-2 might be a promising therapeutic target in the treatment of SSc.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21249544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765391PMC
December 2020

SpikeInterface, a unified framework for spike sorting.

Elife 2020 11 10;9. Epub 2020 Nov 10.

School of Informatics, University of Edinburgh, Edinburgh, United Kingdom.

Much development has been directed toward improving the performance and automation of spike sorting. This continuous development, while essential, has contributed to an over-saturation of new, incompatible tools that hinders rigorous benchmarking and complicates reproducible analysis. To address these limitations, we developed SpikeInterface, a Python framework designed to unify preexisting spike sorting technologies into a single codebase and to facilitate straightforward comparison and adoption of different approaches. With a few lines of code, researchers can reproducibly run, compare, and benchmark most modern spike sorting algorithms; pre-process, post-process, and visualize extracellular datasets; validate, curate, and export sorting outputs; and more. In this paper, we provide an overview of SpikeInterface and, with applications to real and simulated datasets, demonstrate how it can be utilized to reduce the burden of manual curation and to more comprehensively benchmark automated spike sorters.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.61834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704107PMC
November 2020

Respiration and brain neural dynamics associated with interval timing during odor fear learning in rats.

Sci Rep 2020 10 19;10(1):17643. Epub 2020 Oct 19.

Lyon Neuroscience Research Center, INSERM U1028, CNRS UMR 5292, Université Lyon 1, 69366, Lyon, France.

In fear conditioning, where a conditioned stimulus predicts the arrival of an aversive stimulus, the animal encodes the time interval between the two stimuli. Here we monitored respiration to visualize anticipatory behavioral responses in an odor fear conditioning in rats, while recording theta (5-15 Hz) and gamma (40-80 Hz) brain oscillatory activities in the medial prefrontal cortex (mPFC), basolateral amygdala (BLA), dorsomedial striatum (DMS) and olfactory piriform cortex (PIR). We investigated the temporal patterns of respiration frequency and of theta and gamma activity power during the odor-shock interval, comparing two interval durations. We found that akin to respiration patterns, theta temporal curves were modulated by the duration of the odor-shock interval in the four recording sites, and respected scalar property in mPFC and DMS. In contrast, gamma temporal curves were modulated by the interval duration only in the mPFC, and in a manner that did not respect scalar property. This suggests a preferential role for theta rhythm in interval timing. In addition, our data bring the novel idea that the respiratory rhythm might take part in the setting of theta activity dynamics related to timing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-74741-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573637PMC
October 2020

cDC1 are required for the initiation of collagen-induced arthritis.

J Transl Autoimmun 2020 16;3:100066. Epub 2020 Sep 16.

Department of Clinical Immunology and Rheumatology.

Rheumatoid arthritis (RA) is chronic autoimmune disease which etiology remains unknown. Several cell types have been described to potentiate/aggravate the arthritic process however the initiating event in synovial inflammation is still elusive. Dendritic cells (DCs) are essential for the initiation of primary immune responses and thus we hypothesized that these cells might be crucial for RA induction. DCs are a heterogeneous population of cells comprising different subsets with distinct phenotype and function. Here we investigated which DC subset(s) is/are crucial for the initiation of the arthritic process. We have previously demonstrated that Flt3-/- mice, with reduced DCs, were protected from collagen induced arthritis (CIA). Here we have shown that GM-CSF derived DCs in Flt3L-/- mice are functional but not sufficient to induce arthritis. Batf3 mice lacking both CD103 and CD8α cDC1 were resistant to collagen induced arthritis (CIA), demonstrating that this DC subset is crucial for arthritis development. CEP-701 (a Flt3L inhibitor) treatment prevented CIA induction, and reduced dramatically the numbers CD103 cDC1s present in the lymph nodes and synovium. Hence this study identified cDC1 as the main subset orchestrating the initiation of cell-mediated immunity in arthritis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtauto.2020.100066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522802PMC
September 2020

Blocking IL-17: A Promising Strategy in the Treatment of Systemic Rheumatic Diseases.

Int J Mol Sci 2020 Sep 26;21(19). Epub 2020 Sep 26.

Rheumatology & Immuno-Mediated Diseases Research Group (IRIDIS), Galicia Sur Health Research Institute (IIS Galicia Sur). SERGAS-UVIGO, 36201 Vigo, Spain.

Systemic rheumatic diseases are a heterogeneous group of autoimmune disorders that affect the connective tissue, characterized by the involvement of multiple organs, leading to disability, organ failure and premature mortality. Despite the advances in recent years, the therapeutic options for these diseases are still limited and some patients do not respond to the current treatments. Interleukin-17 (IL-17) is a cytokine essential in the defense against extracellular bacteria and fungi. Disruption of IL-17 homeostasis has been associated with the development and progression of rheumatic diseases, and the approval of different biological therapies targeting IL-17 for the treatment of psoriatic arthritis (PsA) and ankylosing spondylitis (AS) has highlighted the key role of this cytokine. IL-17 has been also implicated in the pathogenesis of systemic rheumatic diseases, including systemic lupus erythematosus (SLE), Sjögren's syndrome (SS) and systemic sclerosis (SSc). The aim of this review is to summarize and discuss the most recent findings about the pathogenic role of IL-17 in systemic rheumatic and its potential use as a therapeutic option.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21197100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582977PMC
September 2020

Leukocyte Associated Immunoglobulin Like Receptor 1 Regulation and Function on Monocytes and Dendritic Cells During Inflammation.

Front Immunol 2020 19;11:1793. Epub 2020 Aug 19.

Center for Translational Immunology, University Medical Center Utrecht, University of Utrecht, Utrecht, Netherlands.

Inhibitory receptors are crucial immune regulators and are essential to prevent exacerbated responses, thus contributing to immune homeostasis. Leukocyte associated immunoglobulin like receptor 1 (LAIR-1) is an immune inhibitory receptor which has collagen and collagen domain containing proteins as ligands. LAIR-1 is broadly expressed on immune cells and has a large availability of ligands in both circulation and tissues, implicating a need for tight regulation of this interaction. In the current study, we sought to examine the regulation and function of LAIR-1 on monocyte, dendritic cell (DC) and macrophage subtypes, using different models. We found that LAIR-1 is highly expressed on intermediate monocytes as well as on plasmacytoid DCs. LAIR-1 is also expressed on skin immune cells, mainly on tissue CD14 cells, macrophages and CD1c DCs. , monocyte and type-2 conventional DC stimulation leads to LAIR-1 upregulation, which may reflect the importance of LAIR-1 as negative regulator under inflammatory conditions. Indeed, we demonstrate that LAIR-1 ligation on monocytes inhibits toll like receptor (TLR)4 and Interferon (IFN)-α- induced signals. Furthermore, LAIR-1 is downregulated on GM-CSF and IFN-γ monocyte-derived macrophages and monocyte-derived DCs. In addition, LAIR-1 triggering during monocyte derived-DC differentiation results in significant phenotypic changes, as well as a different response to TLR4 and IFN-α stimulation. This indicates a role for LAIR-1 in skewing DC function, which impacts the cytokine expression profile of these cells. In conclusion, we demonstrate that LAIR-1 is consistently upregulated on monocytes and DC during the inflammatory phase of the immune response and tends to restore its expression during the resolution phase. Under inflammatory conditions, LAIR-1 has an inhibitory function, pointing toward to a potential intervention opportunity targeting LAIR-1 in inflammatory conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.01793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466540PMC
April 2021

Semaphorin4A-Plexin D1 Axis Induces Th2 and Th17 While Represses Th1 Skewing in an Autocrine Manner.

Int J Mol Sci 2020 Sep 22;21(18). Epub 2020 Sep 22.

Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, University of Utrecht, 3508 GA Utrecht, The Netherlands.

Semaphorin (Sema)4A is a transmembrane glycoprotein that is elevated in several autoimmune diseases such as systemic sclerosis, rheumatoid arthritis and multiple sclerosis. Sema4A has a key role in the regulation of Thelper Th1 and Th2 differentiation and we recently demonstrated that CD4 T cell activation induces the expression of Sema4A. However, the autocrine role of Sema4A on Th cell differentiation remains unknown. Naïve Th cells from healthy controls were cell sorted and differentiated into Th1, Th2 and Th17 in the presence or absence of a neutralizing antibody against the Sema4A receptor PlexinD1. Gene expression was determined by quantitative PCR and protein expression by ELISA and flow cytometry. We found that the expression of Sema4A is induced during Th1, Th2 and Th17 differentiation. PlexinD1 neutralization induced the differentiation of Th1 cells, while reduced the Th2 and Th17 skewing. These effects were associated with an upregulation of the transcription factor T-bet by Th1 cells, and to downregulation of GATA3 and RORγt in Th2 cells and Th17 cells, respectively. Finally, PlexinD1 neutralization regulates the systemic sclerosis patients serum-induced cytokine production by CD4 T cells. Therefore, the autocrine Sema4A-PlexinD1 signaling acts as a negative regulator of Th1 skewing but is a key mediator on Th2 and Th17 differentiation, suggesting that dysregulation of this axis might be implicated in the pathogenesis of CD4 T cell-mediated diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21186965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555002PMC
September 2020

Biomarker profiles of endothelial activation and dysfunction in rare systemic autoimmune diseases: implications for cardiovascular risk.

Rheumatology (Oxford) 2021 02;60(2):785-801

Centre for Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands.

Objectives: Vasculopathy is an important hallmark of systemic chronic inflammatory connective tissue diseases (CICTD) and is associated with increased cardiovascular risk. We investigated disease-specific biomarker profiles associated with endothelial dysfunction, angiogenic homeostasis and (tissue) inflammation, and their relation to disease activity in rare CICTD.

Methods: A total of 38 serum proteins associated with endothelial (dys)function and inflammation were measured by multiplex-immunoassay in treatment-naive patients with localized scleroderma (LoS, 30), eosinophilic fasciitis (EF, 8) or (juvenile) dermatomyositis (34), 119 (follow-up) samples during treatment, and 65 controls. Data were analysed by unsupervised clustering, Spearman correlations, non-parametric t test and ANOVA.

Results: The systemic CICTD, EF and dermatomyositis, had distinct biomarker profiles, with 'signature' markers galectin-9 (dermatomyositis) and CCL4, CCL18, CXCL9, fetuin, fibronectin, galectin-1 and TSP-1 (EF). In LoS, CCL18, CXCL9 and CXCL10 were subtly increased. Furthermore, dermatomyositis and EF shared upregulation of markers related to interferon (CCL2, CXCL10), endothelial activation (VCAM-1), inhibition of angiogenesis (angiopoietin-2, sVEGFR-1) and inflammation/leucocyte chemo-attraction (CCL19, CXCL13, IL-18, YKL-40), as well as disturbance of the Angiopoietin-Tie receptor system and VEGF-VEGFR system. These profiles were related to disease activity, and largely normalized during treatment. However, a subgroup of CICTD patients showed continued elevation of CXCL10, CXCL13, galectin-9, IL-18, TNFR2, VCAM-1, and/or YKL-40 during clinically inactive disease, possibly indicating subclinical interferon-driven inflammation and/or endothelial dysfunction.

Conclusion: CICTD-specific biomarker profiles revealed an anti-angiogenic, interferon-driven environment during active disease, with incomplete normalization under treatment. This warrants further investigation into monitoring of vascular biomarkers during clinical follow-up, or targeted interventions to minimize cardiovascular risk in the long term.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/rheumatology/keaa270DOI Listing
February 2021

SpikeForest, reproducible web-facing ground-truth validation of automated neural spike sorters.

Elife 2020 05 19;9. Epub 2020 May 19.

Center for Computational Mathematics, Flatiron Institute, New York, United States.

Spike sorting is a crucial step in electrophysiological studies of neuronal activity. While many spike sorting packages are available, there is little consensus about which are most accurate under different experimental conditions. SpikeForest is an open-source and reproducible software suite that benchmarks the performance of automated spike sorting algorithms across an extensive, curated database of ground-truth electrophysiological recordings, displaying results interactively on a continuously-updating website. With contributions from eleven laboratories, our database currently comprises 650 recordings (1.3 TB total size) with around 35,000 ground-truth units. These data include paired intracellular/extracellular recordings and state-of-the-art simulated recordings. Ten of the most popular spike sorting codes are wrapped in a Python package and evaluated on a compute cluster using an automated pipeline. SpikeForest documents community progress in automated spike sorting, and guides neuroscientists to an optimal choice of sorter and parameters for a wide range of probes and brain regions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.55167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237210PMC
May 2020

Kinetic Isotope Effect as a Tool To Investigate the Oxygen Reduction Reaction on Pt-based Electrocatalysts - Part II: Effect of Platinum Dispersion.

Chemphyschem 2020 Jun 27;21(12):1331-1339. Epub 2020 May 27.

Department of Chemical & Biomolecular Engineering, National Fuel Cell Research Center (NFCRC), University of California, Irvine, CA 92697, USA.

We investigated the oxygen reduction reaction (ORR) mechanism on Pt nanoparticles (NPs) dispersed on several carbon blacks with various physicochemical properties (i. e. specific surface ranging from 80 to 900 m  g , different graphitization degree, etc.). Using the kinetic isotope effect (KIE) along with various electrochemical characterizations, we determined that the rate determining step (RDS) of the ORR is a proton-independent step when the density of Pt NPs on the surface of the carbon support is high. Upon decrease of the density of Pt NPs on the surface, the RDS of the ORR starts involving a proton, as denoted by an increase of the KIE >1. This underlined the critical role played by the carbon support in the oxygen reduction reaction electrocatalysis by Pt supported on high surface area carbon.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cphc.201901092DOI Listing
June 2020

: Neuroscience Tool for Interactive Characterization.

eNeuro 2020 May/Jun;7(3). Epub 2020 May 11.

Departments of Biology, Neurosciences, and Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106-7080.

A software tool for synchronization of video with signals would be of broad general use to behavioral neuroscientists. A new program, called (NEUROscience Tool for Interactive Characterization), allows users to review and annotate signal data synchronized with video, performs simple initial analyses including signal filtering and spike detection, is easy to use, and supports a variety of file formats. The program also facilitates collaborations by using a portable specification for loading and processing data and retrieving data files from online sources. Two examples are shown in which the software is used to explore experimental datasets with extracellular nerve or muscle recordings and simultaneous video of behavior. The configuration specification for controlling how data are located, loaded, processed, and plotted is also summarized. Algorithms for spike detection and burst detection are demonstrated. This new program could be used in many applications in which behavior and signals need to be analyzed together.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/ENEURO.0085-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215586PMC
June 2021

High beta rhythm amplitude in olfactory learning signs a well-consolidated and non-flexible behavioral state.

Sci Rep 2019 12 30;9(1):20259. Epub 2019 Dec 30.

Lyon Neuroscience Research Center, Inserm U 1028, CNRS UMR 5292, University Lyon 1, Bron, 69675, France.

Beta rhythm (15-30 Hz) is a major candidate underlying long-range communication in the brain. In olfactory tasks, beta activity is strongly modulated by learning but its condition of expression and the network(s) responsible for its generation are unclear. Here we analyzed the emergence of beta activity in local field potentials recorded from olfactory, sensorimotor and limbic structures of rats performing an olfactory task. Rats performed successively simple discrimination, rule transfer, memory recall tests and contingency reversal. Beta rhythm amplitude progressively increased over learning in most recorded areas. Beta amplitude reduced to baseline when new odors were introduced, but remained high during memory recall. Intra-session analysis showed that even expert rats required several trials to reach a good performance level, with beta rhythm amplitude increasing in parallel. Notably, at the beginning of the reversal task, beta amplitude remained high while performance was low and, in all tested animals, beta amplitude decreased before rats were able to learn the new contingencies. Connectivity analysis showed that beta activity was highly coherent between all structures where it was expressed. Overall, our results suggest that beta rhythm is expressed in a highly coherent network when context learning - including both odors and reward - is consolidated and signals behavioral inflexibility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-56340-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937317PMC
December 2019

Extracellular SPARC cooperates with TGF-β signalling to induce pro-fibrotic activation of systemic sclerosis patient dermal fibroblasts.

Rheumatology (Oxford) 2020 09;59(9):2258-2263

Department of Rheumatology and Clinical Immunology.

Objectives: SSc is an autoimmune disease characterized by inflammation, vascular injury and excessive fibrosis in multiple organs. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein that regulates processes involved in SSc pathology, such as inflammation and fibrosis. In vivo and in vitro studies have implicated SPARC in SSc, but it is unclear if the pro-fibrotic effects of SPARC on fibroblasts are a result of intracellular signalling or fibroblast interactions with extracellular SPARC hampering further development of SPARC as a potential therapeutic target. This study aimed to analyse the potential role of exogenous SPARC as a regulator of fibrosis in SSc.

Methods: Dermal fibroblasts from both healthy controls and SSc patients were stimulated with SPARC alone or in combination with TGF-β1, in the absence or presence of a TGF receptor 1 inhibitor. mRNA and protein expression of extracellular matrix components and other fibrosis-related mediators were measured by quantitative PCR and western blot.

Results: Exogenous SPARC induced mRNA and protein expression of collagen I, collagen IV, fibronectin 1, TGF-β and SPARC by dermal fibroblasts from SSc patients, but not from healthy controls. Importantly, exogenous SPARC induced the activation of the tyrosine kinase SMAD2 and pro-fibrotic gene expression induced by SPARC in SSc fibroblasts was abrogated by inhibition of TGF-β signalling.

Conclusion: These results indicate that exogenous SPARC is an important pro-fibrotic mediator contributing to the pathology driving SSc but in a TGF-β dependent manner. Therefore, SPARC could be a promising therapeutic target for reducing fibrosis in SSc patients, even in late states of the disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/rheumatology/kez583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449812PMC
September 2020

Promotion of macrophage activation by Tie2 in the context of the inflamed synovia of rheumatoid arthritis and psoriatic arthritis patients.

Rheumatology (Oxford) 2020 02;59(2):426-438

Department of Rheumatology and Clinical Immunology, University of Utrecht, Utrecht.

Objective: To examine the role of Tie2 signalling in macrophage activation within the context of the inflammatory synovial microenvironment present in patients with RA and PsA.

Methods: Clinical responses and macrophage function were examined in wild-type and Tie2-overexpressing (Tie2-TG) mice in the K/BxN serum transfer model of arthritis. Macrophages derived from peripheral blood monocytes from healthy donors, RA and PsA patients, and RA and PsA synovial tissue explants were stimulated with TNF (10 ng/ml), angiopoietin (Ang)-1 or Ang-2 (200 ng/ml), or incubated with an anti-Ang2 neutralizing antibody. mRNA and protein expression of inflammatory mediators was analysed by quantitative PCR, ELISA and Luminex.

Results: Tie2-TG mice displayed more clinically severe arthritis than wild-type mice, accompanied by enhanced joint expression of IL6, IL12B, NOS2, CCL2 and CXCL10, and activation of bone marrow-derived macrophages in response to Ang-2 stimulation. Ang-1 and Ang-2 significantly enhanced TNF-induced expression of pro-inflammatory cytokines and chemokines in macrophages from healthy donors differentiated with RA and PsA SF and peripheral blood-derived macrophages from RA and PsA patients. Both Ang-1 and Ang-2 induced the production of IL-6, IL-12p40, IL-8 and CCL-3 in synovial tissue explants of RA and PsA patients, and Ang-2 neutralization suppressed the production of IL-6 and IL-8 in the synovial tissue of RA patients.

Conclusion: Tie2 signalling enhances TNF-dependent activation of macrophages within the context of ongoing synovial inflammation in RA and PsA, and neutralization of Tie2 ligands might be a promising therapeutic target in the treatment of these diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/rheumatology/kez315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571483PMC
February 2020

Predicted temperature-increase-induced global health burden and its regional variability.

Environ Int 2019 10 24;131:105027. Epub 2019 Jul 24.

Department of Environmental Health, National Institute of Public Health, Cuernavaca, Morelos, Mexico.

An increase in the global health burden of temperature was projected for 459 locations in 28 countries worldwide under four representative concentration pathway scenarios until 2099. We determined that the amount of temperature increase for each 100 ppm increase in global CO concentrations is nearly constant, regardless of climate scenarios. The overall average temperature increase during 2010-2099 is largest in Canada (1.16 °C/100 ppm) and Finland (1.14 °C/100 ppm), while it is smallest in Ireland (0.62 °C/100 ppm) and Argentina (0.63 °C/100 ppm). In addition, for each 1 °C temperature increase, the amount of excess mortality is increased largely in tropical countries such as Vietnam (10.34%p/°C) and the Philippines (8.18%p/°C), while it is decreased in Ireland (-0.92%p/°C) and Australia (-0.32%p/°C). To understand the regional variability in temperature increase and mortality, we performed a regression-based modeling. We observed that the projected temperature increase is highly correlated with daily temperature range at the location and vulnerability to temperature increase is affected by health expenditure, and proportions of obese and elderly population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.envint.2019.105027DOI Listing
October 2019

Low RUNX3 expression alters dendritic cell function in patients with systemic sclerosis and contributes to enhanced fibrosis.

Ann Rheum Dis 2019 09 24;78(9):1249-1259. Epub 2019 May 24.

Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands

Objectives: Systemic sclerosis (SSc) is an autoimmune disease with unknown pathogenesis manifested by inflammation, vasculopathy and fibrosis in skin and internal organs. Type I interferon signature found in SSc propelled us to study plasmacytoid dendritic cells (pDCs) in this disease. We aimed to identify candidate pathways underlying pDC aberrancies in SSc and to validate its function on pDC biology.

Methods: In total, 1193 patients with SSc were compared with 1387 healthy donors and 8 patients with localised scleroderma. PCR-based transcription factor profiling and methylation status analyses, single nucleotide polymorphism genotyping by sequencing and flow cytometry analysis were performed in pDCs isolated from the circulation of healthy controls or patients with SSc. pDCs were also cultured under hypoxia, inhibitors of methylation and hypoxia-inducible factors and runt-related transcription factor 3 (RUNX3) levels were determined. To study Runx3 function, -Cre: mice were used in in vitro functional assay and bleomycin-induced SSc skin inflammation and fibrosis model.

Results: Here, we show downregulation of transcription factor RUNX3 in SSc pDCs. A higher methylation status of the gene, which is associated with polymorphism rs6672420, correlates with lower expression and SSc susceptibility. Hypoxia is another factor that decreases level in pDC. Mouse pDCs deficient of show enhanced maturation markers on CpG stimulation. In vivo, deletion of in dendritic cell leads to spontaneous induction of skin fibrosis in untreated mice and increased severity of bleomycin-induced skin fibrosis.

Conclusions: We show at least two pathways potentially causing low RUNX3 level in SSc pDCs, and we demonstrate the detrimental effect of loss of in SSc model further underscoring the role of pDCs in this disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/annrheumdis-2018-214991DOI Listing
September 2019

New Insights from 22-kHz Ultrasonic Vocalizations to Characterize Fear Responses: Relationship with Respiration and Brain Oscillatory Dynamics.

eNeuro 2019 Mar/Apr;6(2). Epub 2019 May 7.

Lyon Neuroscience Research Center, Institut National de la Santé et de la Recherche Médicale Unité 1028, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5292, University Lyon 1, Lyon 69366, France

Fear behavior depends on interactions between the medial prefrontal cortex (mPFC) and the basolateral amygdala (BLA), and the expression of fear involves synchronized activity in θ and γ oscillatory activities. In addition, freezing, the most classical measure of fear response in rodents, temporally coincides with the development of sustained 4-Hz oscillations in prefrontal-amygdala circuits. Interestingly, these oscillations were recently shown to depend on the animal's respiratory rhythm, supporting the growing body of evidence pinpointing the influence of nasal breathing on brain rhythms. During fearful states, rats also emit 22-kHz ultrasonic vocalizations (USVs) which drastically affect respiratory rhythm. However, the relationship between 22-kHz USV, respiration, and brain oscillatory activities is still unknown. Yet such information is crucial for a comprehensive understanding of how the different components of fear response collectively modulate rat's brain neural dynamics. Here, we trained male rats in an odor fear conditioning task, while recording simultaneously local field potentials (LFPs) in BLA, mPFC, and olfactory piriform cortex (PIR), together with USV calls and respiration. We show that USV calls coincide with an increase in delta and gamma power and a decrease in theta power. In addition, during USV emission in contrast to silent freezing, there is no coupling between respiratory rate and delta frequency, and the modulation of fast oscillations amplitude relative to the phase of respiration is modified. We propose that sequences of USV calls could result in a differential gating of information within the network of structures sustaining fear behavior, thus potentially modulating fear expression/memory.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/ENEURO.0065-19.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506822PMC
February 2020

Induction of Inflammation and Fibrosis by Semaphorin 4A in Systemic Sclerosis.

Arthritis Rheumatol 2019 10 27;71(10):1711-1722. Epub 2019 Aug 27.

University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands.

Objective: To analyze the potential role of semaphorin 4A (Sema4A) in inflammatory and fibrotic processes involved in the pathology of systemic sclerosis (SSc).

Methods: Sema4A levels in the plasma of healthy controls (n = 11) and SSc patients (n = 20) were determined by enzyme-linked immunosorbent assay (ELISA). The expression of Sema4A and its receptors in monocytes and CD4+ T cells from healthy controls and SSc patients (n = 6-7 per group) was determined by ELISA and flow cytometry. Th17 cytokine production by CD4+ T cells (n = 5-7) was analyzed by ELISA and flow cytometry. The production of inflammatory mediators and extracellular matrix (ECM) components by dermal fibroblast cells (n = 6) was analyzed by quantitative polymerase chain reaction, ELISA, Western blotting, confocal microscopy, and ECM deposition assay.

Results: Plasma levels of Sema4A, and Sema4A expression by circulating monocytes and CD4+ T cells, were significantly higher in SSc patients than in healthy controls (P < 0.05). Inflammatory mediators significantly up-regulated the secretion of Sema4A by monocytes and CD4+ T cells from SSc patients (P < 0.05 versus unstimulated SSc cells). Functional assays showed that Sema4A significantly enhanced the expression of Th17 cytokines induced by CD3/CD28 in total CD4+ T cells as well in different CD4+ T cell subsets (P < 0.05 versus unstimulated SSc cells). Finally, Sema4A induced a profibrotic phenotype in dermal fibroblasts from both healthy controls and SSc patients, which was abrogated by blocking or silencing the expression of Sema4A receptors.

Conclusion: Our findings indicate that Sema4A plays direct and dual roles in promoting inflammation and fibrosis, 2 main features of SSc, suggesting that Sema4A might be a novel therapeutic target in SSc.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/art.40915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790618PMC
October 2019

Role of Semaphorins in Immunopathologies and Rheumatic Diseases.

Authors:
Samuel Garcia

Int J Mol Sci 2019 Jan 16;20(2). Epub 2019 Jan 16.

Department of Rheumatology and Clinical Immunology and Laboratory of Translational Immunology, University Medical Center Utrecht, University of Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.

Rheumatic diseases are disorders characterized by joint inflammation, in which other organs are also affected. There are more than two hundred rheumatic diseases, the most studied so far are rheumatoid arthritis, osteoarthritis, spondyloarthritis, systemic lupus erythematosus, and systemic sclerosis. The semaphorin family is a large group of proteins initially described as axon guidance molecules involved in nervous system development. Studies have demonstrated that semaphorins play a role in other processes such as the regulation of immunity, angiogenesis, bone remodeling, apoptosis, and cell migration and invasion. Moreover, semaphorins have been related to the pathogenesis of multiple sclerosis, asthma, Alzheimer, myocarditis, atherosclerosis, fibrotic diseases, osteopetrosis, and cancer. The aim of this review is to summarize current knowledge regarding the role of semaphorins in rheumatic diseases, and discuss their potential applications as therapeutic targets to treat these disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms20020374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359241PMC
January 2019

Class 3 semaphorins modulate the invasive capacity of rheumatoid arthritis fibroblast-like synoviocytes.

Rheumatology (Oxford) 2018 05;57(5):909-920

Department of Experimental Immunology and Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Objective: Class 3 semaphorins regulate diverse cellular processes relevant to the pathology of RA, including immune modulation, angiogenesis, apoptosis and invasive cell migration. Therefore, we analysed the potential role of class 3 semaphorins in the pathology of RA.

Methods: Protein and mRNA expression in RA synovial tissue, SF and fibroblast-like synoviocytes (FLS) were determined by immunoblotting and quantitative PCR (qPCR). RA FLS migration and invasion were determined using wound closure and transwell invasion assays, respectively. PlexinA1, neuropilin-1 and neuropilin-2 expression was knocked down using small interfering RNA (siRNA). Activation of FLS intracellular signalling pathways was assessed by immunoblotting.

Results: mRNA expression of semaphorins (Sema)3B, Sema3C, Sema3F and Sema3G was significantly lower in the synovial tissue of early arthritis patients at baseline who developed persistent disease compared with patients with self-limiting disease after 2 years follow-up. Sema3B and Sema3F expression was significantly lower in arthritis patients fulfilling classification criteria for RA compared with those who did not. FLS expression of Sema3A was induced after stimulation with TNF, IL-1β or lipopolysaccharides (LPS), while Sema3B and Sema3F expression was downregulated. Exogenously applied Sema3A induced the migration and invasive capacity of FLS, while stimulation with Sema3B or Sema3F reduced spontaneous FLS migration, and platelet-derived growth factor induced cell invasion, effects associated with differential regulation of MMP expression and mediated by the PlexinA1 and neuropilin-1 and -2 receptors.

Conclusion: Our data suggest that modulation of class 3 semaphorin signaling could be a novel therapeutic strategy for modulating the invasive behaviour of FLS in RA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/rheumatology/kex511DOI Listing
May 2018

Neuronal dynamics supporting formation and recombination of cross-modal olfactory-tactile association in the rat hippocampal formation.

J Neurophysiol 2018 03 6;119(3):1140-1152. Epub 2017 Dec 6.

Team CMO: Olfaction from Coding to Memory, Centre de Recherche en Neuroscience de Lyon, CNRS UMR 5292, INSERM U1028, Université Lyon 1, Université de Lyon , Lyon , France.

The present study is aimed at describing some aspects of the neural dynamics supporting discrimination of olfactory-tactile paired-associated stimuli during acquisition of new pairs and during recombination of previously learned pairs in the rat. To solve the task, animals have to identify one odor-texture (OT) combination associated with a food reward among three cups with overlapping elements. Previous experiments demonstrated that the lateral entorhinal cortex (LEC) is involved in the processes underlying OT acquisition, whereas the dorsal hippocampus (DH) is selectively involved in the recombination processes. In the present study, local field potentials were recorded form the anterior piriform cortex (aPC), LEC, and DH in freely moving rats performing these tasks. Signal analysis focused on theta (5-12 Hz)- and beta-band (15-40 Hz) oscillatory activities in terms of both amplitude and synchrony. The results show that cue sampling was associated with a significant increase in the beta-band activity during the choice period in both the aPC and the LEC, and is modulated by level of expertise and the animal's decision. In addition, this increase was significantly higher during the recombination compared with the acquisition of the OT task, specifically when animals had to neglect the odor previously associated with the reward. Finally, a significant decrease in coherence in the theta band between LEC and DH was observed in the recombination but not in the acquisition task. These data point to specific neural signatures of simple and complex cross-modal sensory processing in the LEC-DH complex. NEW & NOTEWORTHY This study is the first to describe electrophysiological correlates of cross-modal olfactory-tactile integration in rats. Recordings were sought from the lateral entorhinal cortex and the dorsal hippocampus because previous studies have shown their role in the formation and in the recombination of previously learned associations. We identified specific oscillatory-evoked neural responses in these structures in the theta and beta bands, which characterize acquisition and recombination of cross-modal olfactory-tactile pairs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/jn.00666.2017DOI Listing
March 2018

CXCL4 is a novel inducer of human Th17 cells and correlates with IL-17 and IL-22 in psoriatic arthritis.

Eur J Immunol 2018 03 15;48(3):522-531. Epub 2018 Jan 15.

Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

CXCL4 regulates multiple facets of the immune response and is highly upregulated in various Th17-associated rheumatic diseases. However, whether CXCL4 plays a direct role in the induction of IL-17 production by human CD4 T cells is currently unclear. Here, we demonstrated that CXCL4 induced human CD4 T cells to secrete IL-17 that co-expressed IFN-γ and IL-22, and differentiated naïve CD4 T cells to become Th17-cytokine producing cells. In a co-culture system of human CD4 T cells with monocytes or myeloid dendritic cells, CXCL4 induced IL-17 production upon triggering by superantigen. Moreover, when monocyte-derived dendritic cells were differentiated in the presence of CXCL4, they orchestrated increased levels of IL-17, IFN-γ, and proliferation by CD4 T cells. Furthermore, the CXCL4 levels in synovial fluid from psoriatic arthritis patients strongly correlated with IL-17 and IL-22 levels. A similar response to CXCL4 of enhanced IL-17 production by CD4 T cells was also observed in patients with psoriatic arthritis. Altogether, we demonstrate that CXCL4 boosts pro-inflammatory cytokine production especially IL-17 by human CD4 T cells, either by acting directly or indirectly via myeloid antigen presenting cells, implicating a role for CXCL4 in PsA pathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/eji.201747195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5888178PMC
March 2018

Heat Wave and Mortality: A Multicountry, Multicommunity Study.

Environ Health Perspect 2017 08 10;125(8):087006. Epub 2017 Aug 10.

Laboratory of Experimental Air Pollution, Department of Pathology, School of Medicine, University of São Paulo , São Paulo, Brazil.

Background: Few studies have examined variation in the associations between heat waves and mortality in an international context.

Objectives: We aimed to systematically examine the impacts of heat waves on mortality with lag effects internationally.

Methods: We collected daily data of temperature and mortality from 400 communities in 18 countries/regions and defined 12 types of heat waves by combining community-specific daily mean temperature ≥90th, 92.5th, 95th, and 97.5th percentiles of temperature with duration ≥2, 3, and 4 d. We used time-series analyses to estimate the community-specific heat wave-mortality relation over lags of 0-10 d. Then, we applied meta-analysis to pool heat wave effects at the country level for cumulative and lag effects for each type of heat wave definition.

Results: Heat waves of all definitions had significant cumulative associations with mortality in all countries, but varied by community. The higher the temperature threshold used to define heat waves, the higher heat wave associations on mortality. However, heat wave duration did not modify the impacts. The association between heat waves and mortality appeared acutely and lasted for 3 and 4 d. Heat waves had higher associations with mortality in moderate cold and moderate hot areas than cold and hot areas. There were no added effects of heat waves on mortality in all countries/regions, except for Brazil, Moldova, and Taiwan. Heat waves defined by daily mean and maximum temperatures produced similar heat wave-mortality associations, but not daily minimum temperature.

Conclusions: Results indicate that high temperatures create a substantial health burden, and effects of high temperatures over consecutive days are similar to what would be experienced if high temperature days occurred independently. People living in moderate cold and moderate hot areas are more sensitive to heat waves than those living in cold and hot areas. Daily mean and maximum temperatures had similar ability to define heat waves rather than minimum temperature. https://doi.org/10.1289/EHP1026.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1289/EHP1026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5783630PMC
August 2017

Insight into the Endocrine System and the Immune System: A Review of the Inflammatory Role of Prolactin in Rheumatoid Arthritis and Psoriatic Arthritis.

Front Immunol 2017 23;8:720. Epub 2017 Jun 23.

Laboratory of Translational Immunology, Department of Rheumatology and Clinical Immunology, University Medical Center, Utrecht, Netherlands.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects females three times more frequently than males. A potential role for hormones, such as prolactin (PRL), may in part explain this phenomenon. The risk of developing RA is increased in women who are lactating after the first pregnancy, which might be related to breastfeeding and the release of PRL. Other studies found a protective effect of PRL on RA development. Some studies have reported that hyperprolactinemia is more common in RA and serum PRL levels are correlated with several disease parameters, although others could not confirm these findings. Overall the plasma PRL levels are on average not elevated in RA. Previously, a small number of open-label clinical trials using bromocriptine, which indirectly decreases PRL levels, were performed in RA patients and showed clinical benefit, although others found the opposite effect. Locally produced PRL at the site of inflammation may have a crucial role in RA as well, as it has been shown that PRL can be produced by synovial macrophages. Locally produced PRL has both pro-inflammatory and anti-inflammatory effects in arthritis. Psoriatic arthritis (PsA) is also an autoinflammatory disease, in which the prolactin receptor is also expressed in macrophages. The aim of this review is to provide an overview of the potential role of PRL signaling in inflammatory joint diseases (RA and PsA) and its potential as a therapeutic target.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2017.00720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5481306PMC
June 2017
-->