Impact des extraits organiques de particules diesel (DEPe) sur la physiologie de macrophages humains polarisés in vitro

Macrophages (MΦ), well-known to play a key role in immune response, also respond to environmental toxic chemicals such as diesel exhaust particles (DEP), an air pollutant recently classified as carcinogenic to humans. MΦ are heterogeneous and plastic cells which activate according to their microenvironment into either an M1 subtype (so called classically activated or pro-inflammatory) under IFNγ and LPS stimulation or an M2 subtype (so called alternatively activated or anti-inflammatory) under IL-4 and/or IL-13 stimulation. However, potential effects of DEPs on M1/M2 MΦ polarization remain poorly documented. First, we characterized the expression marker of in vitro M-CSF-differentiated MΦ from human monocytes and activated into the M1 or M2 subtypes. Our main results show that M-CSF-generated MΦ considered as anti-inflammatory are actually able to switch to an M1 phenotype after IFNγ/LPS stimulation. Furthermore, the markers identified in this study were used to assess the impact of organic extracts of DEP (DEPe) on MΦ polarization and more generally on their physiology. DEPe alter some M1 and M2 markers expressed by polarized MΦ, without causing the overall inhibition of the M1 and M2 polarization process or the switch to a different phenotype. This phenotype alteration is associated with a decrease in the LPS-dependent inflammatory response in M1 MΦ and the chemotactic capacities in M2 MΦ. DEPe decrease the secretion of some cytokines and chemokines such as IL-6, IL-12p40 and CCL18 via AhR and/or Nrf2 activation. At the same time, we show that M1 and M2 MΦ in response to DEPe are able to secrete a sufficient level of a pro-fibrotic growth factor, the platelet derived growth factor B (PDGF-B) via AhR activation, leading to stimulation of lung fibroblast proliferation. Finally, these works show that DEPe have immunotoxic properties with regards to the physiology of human in vitro polarized MΦ. This immunotoxicity may then contribute to the deleterious effects of these urban environmental contaminants on human health.Les macrophages (MΦ), des cellules clefs de la réponse immunitaire peuvent répondre à des contaminants environnementaux comme les particules diesel (DEP), des polluants atmosphériques récemment classés cancérigènes pour l'Homme. Les MΦ sont des cellules hétérogènes et plastiques qui s'activent en fonction de leur microenvironnement soit en MΦ M1 (dits classiquement activés ou pro-inflammatoires) sous l'effet de l'INFγ et du LPS soit en MΦ M2 (dits alternativement activés ou réparateurs) sous l'effet de l'IL-4 et/ou de l'IL-13. Les effets des DEP sur la polarisation M1/M2 des MΦ restent peu documentés. Nous avons dans un premier temps caractérisé l'expression des marqueurs des MΦ différenciés in vitro en présence de M-CSF à partir de monocytes humains et polarisés en sous-type M1 ou M2. Nos principaux résultats montrent que les MΦ différenciés au M-CSF considérés comme des MΦ anti-inflammatoires, sont en réalité capables de s'activer vers un phénotype M1 après une stimulation au LPS/IFNγ. De plus, les marqueurs mis en évidence au cours de ce travail ont permis d'évaluer l'impact d'extraits organiques de DEP (DEPe) sur la polarisation des MΦ et plus généralement sur leur physiologie. Les DEPe altèrent l'expression de certains marqueurs M1 et M2 des MΦ, sans toutefois provoquer d'inhibition globale des processus de polarisation M1 et M2 ou de transition d'un phénotype vers un autre. Cette altération du phénotype est associée à une diminution de la réponse inflammatoire LPS-dépendante dans les MΦ M1 et des capacités chimiotactiques des MΦ M2. Les DEPe diminuent la sécrétion de certaines cytokines et chimiokines comme l'IL-6, l'IL-12p40 et le CCL18 via l'activation d'AhR et/ou de Nrf2. Parallèlement, nous montrons que les MΦ M1 et M2 exposés aux DEPe sécrètent le platelet deried growth factor B (PDGF-B), un facteur de croissance profibrosant, via l'activation d'AhR en quantité suffisante pour stimuler la prolifération de fibroblastes pulmonaires. Au total, ces travaux démontrent que les DEP possèdent des propriétés immunotoxiques vis-à-vis de la physiologie des macrophages humains polarisés in vitro. Cette immunotoxicité pourrait participer aux effets délétères de ces contaminants environnementaux urbains sur la santé humaine

Pop-down tectonics, fluid channelling and ore deposits within ancient hot orogens

International audienceMany Archaean and Paleoproterozoic deformation zones, often rich in ore resources, show particular structural patterns in particularmarked by regional vertical stretch. These zones are not restricted to greenstone-bearing Archaean domains that may have suffered gravity-driven sagduction of heavy supra-crustals, as extensively discussed since the last twenties. Structures are actually best explained by pop-down tectonics of upper-crustal unitswithin an underlyingweak crust submitted to horizontal regional shortening.Herewe present three complementary examples fromtwo Archaean greenstone belts (Abitibi sub-Province, Quebec, andMurchison belt, South Africa) and one greenstone-lacking Paleoproterozoic belt (Thompson belt,Manitoba). In the three examples, ore is concentrated along steeply dipping deformation zones, rich in syntectonic deposits and marked by substantial sub-vertical crustal stretch. On the other hand, the three regions show differences in age, in metamorphic grade (from sub-greenschist facies to upper amphibolite facies), in metal contents (gold, antimony, nickel), in metal sources, transfers and concentration histories. Our compared analysis emphasizes that pop-down tectonics associatedwith horizontal shortening of weak lithospheres may account for observed geometric patterns and provide a new and promising frame for the analysis of relationships between structural patterns and ore concentrations within old cratons

Metallogeny of precious and base metal mineralization in the Murchison Greenstone Belt, South Africa: indications from U-Pb and Pb-Pb geochronology

International audienceThe 3.09 to 2.97 Ga Murchison Greenstone Belt is an important metallotect in the northern Kaapvaal Craton (South Africa), hosting several precious and base metal deposits. Central to the metallotect is the Antimony Line, striking ENE for over 35 km, which hosts a series of structurally controlled Sb-Au deposits. To the north of the Antimony Line, hosted within felsic volcanic rocks, is the Copper-Zinc Line where a series of small, ca. 2.97 Ga Cu-Zn volcanogenic massive sulfide (VMS)-type deposits occur. New data are provided for the Malati Pump gold mine, located at the eastern end of the Antimony Line. Crystallizations of a granodiorite in the Malati Pump Mine and of the Baderoukwe granodiorite are dated at 2,964 ± 7 and 2,970 ± 7 Ma, respectively (zircon U-Pb), while pyrite associated with gold mineralization yielded a Pb-Pb age of 2,967 ± 48 Ma. Therefore, granodiorite emplacement, sulfide mineral deposition and gold mineralization all happened at ca. 2.97 Ga. It is, thus, suggested that the major styles of orogenic Au-Sb and the Cu-Zn VMS mineralization in the Murchison Greenstone Belt are contemporaneous and that the formation of meso- to epithermal Au-Sb mineralization at fairly shallow levels was accompanied by submarine extrusion of felsic volcanic rocks to form associated Cu-Zn VMS mineralization

The Murchison Greenstone Belt, South Africa: Accreted slivers with contrasting metamorphic conditions

International audienceThis paper presents new petrological and geochronological data for the ∼3.09-2.92 Ga Murchison Greenstone Belt (MGB), located in South Africa's Kaapvaal Craton, and discusses their geotectonic implications. The MGB is made of three tectono-metamorphic units: the Silwana Amphibolites, the Murchison Unit and the La France Formation. They underwent contrasting clockwise pressure-temperature-deformation (P-T-D) histories, and are separated from each other by relatively narrow, high-strain shear zones, with a sinistral, transpressive top-to-the-south movement, consistent with the deformation patterns observed throughout the belt. These patterns are explained by a N-S compressional stress field, affecting the Murchison Belt between 2.97 and 2.92 Ga. Results of new petrological investigations indicate that ultramafic to felsic volcano-sedimentary rocks of the Murchison Unit underwent a greenschist- to lower-amphibolite-facies metamorphism at maximum P-T conditions of 5.6 ± 0.6 kbar at 570 °C, along a relatively hot, minimum apparent geotherm of ∼30 °C/km. In contrast, the Silwana Amphibolites and the La France Formation were metamorphosed at much higher peak metamorphic conditions of 8.7-10 kbar, 630-670 °C, and 8-9 kbar, 600-650 °C, respectively, and require a colder apparent geotherm of ∼20 °C/km. A retrograde, nearly isothermal-decompression P-T path followed by isobaric cooling is also inferred for the La France Formation. The timing of the structural-metamorphic overprint is bracketed between 2.97 and 2.90 Ga, which is constrained by U-Pb zircon ages of a syn-deformation granite within the Murchison Unit and the post-deformation Maranda granite, respectively. Monazite and xenotime from La France metapelites yield much younger ages of ca. 2.75 Ga, with few inherited components at 2.92 Ga. They point to a later activation of the MGB, perhaps related with tectono-thermal events in the Rooiwater Complex and the Pietersburg Greenstone Belt. The relatively cold apparent geotherms recorded in the Silwana and La France rocks, the contrasted peak P-T conditions between the different units, and the near isothermal decompression of the La France Formation indicate that the Kaapvaal craton crust must have been cold enough to enable significant crustal thickening and strain localisation along narrow shear zones and, as a consequence, fast tectonic juxtaposition of rocks metamorphosed at different crustal depths. These features are similar to those observed along Palaeozoic or modern day, oblique subduction-collision zones, but different to those of hot Archaean provinces. We therefore interpret the MGB as representing part of an oblique collision-zone between two terrains of the Kaapvaal craton: the Witwatersrand and Pietersburg terrains

Mavrilimumab, a fully human granulocyte-macrophage colony-stimulating factor receptor α monoclonal antibody: long-term safety and efficacy in patients with rheumatoid arthritis

Objective: Mavrilimumab, a human monoclonal antibody, targets granulocyte-macrophage colony-stimulating factor receptor alpha. We report mavrilimumab long-term safety and efficacy in rheumatoid arthritis patients in two phase IIb studies (1071, 1107) and open-label extension (OLE; NCT01712399). Methods: In 1071, patients with disease-modifying antirheumatic drug (DMARD)-inadequate responses received mavrilimumab 30, 100, 150 mg, or placebo every other week (eow), plus methotrexate. In 1107, patients with anti-tumor necrosis factor agent- and/or DMARD-inadequate responses received mavrilimumab 100 mg eow or golimumab 50 mg every 4 weeks, plus methotrexate. Patients entering the OLE received mavrilimumab 100 mg eow plus methotrexate. Mavrilimumab long-term safety and efficacy were assessed. Results: In total, 442 patients received mavrilimumab (14/245 patients from 1071, 9/70 from 1107, 52/397 from OLE discontinued mavrilimumab treatment throughout the studies). The cumulative safety exposure was 899 patient-years (PY); the median duration of mavrilimumab treatment was 2.5 (range 0.1–3.3) years. Most common treatment-emergent adverse events were nasopharyngitis (n=69, 7.68/100 PY), bronchitis (n=51, 5.68/100 PY). At Weeks 74/104: 3.5%/6.2% patients showed reduction in forced expiratory volume in 1 second; 2.9%/3.4% patients showed reduction in forced vital capacity, respectively (>20% reduction from baseline to <80% predicted). Most pulmonary changes were transient and only infrequently associated with adverse events. Mavrilimumab 100 mg eow demonstrated sustained efficacy; 65.0% and 40.6% patients achieved Disease Activity Score 28–C-reactive protein <3.2 and <2.6, respectively at Week 122. Conclusion: Mavrilimumab long-term treatment maintained response and was well-tolerated with no TEAE incidence increase. Safety data were comparable with both phase IIb qualifying studies

Ionizing radiation modulates human macrophages towards a pro-inflammatory phenotype preserving their pro-invasive and pro-angiogenic capacities

In order to improve the efficacy of conventional radiotherapy, attention has been paid to immune cells, which not only modulate cancer cell response to therapy but are also highly recruited to tumours after irradiation. Particularly, the effect of ionizing radiation on macrophages, using therapeutically relevant doses, is not well understood. To evaluate how radiotherapy affects macrophage behaviour and macrophage-mediated cancer cell activity, human monocyte derived-macrophages were subjected, for a week, to cumulative ionizing radiation doses, as used during cancer treatment (2Gy/fraction/day). Irradiated macrophages remained viable and metabolically active, despite DNA damage. NF-kappaB transcription activation and increased Bcl-xL expression evidenced the promotion of pro-survival activity. A significant increase of pro-inflammatory macrophage markers CD80, CD86 and HLA-DR, but not CCR7, TNF and IL1B was observed after 10Gy cumulative doses, while anti-inflammatory markers CD163, MRC1, VCAN and IL-10 expression decreased, suggesting the modulation towards a more proinflammatory phenotype. Moreover, ionizing radiation induced macrophage morphological alterations and increased their phagocytic rate, without affecting matrix metalloproteases (MMP)2 and MMP9 activity. Importantly, irradiated macrophages promoted cancer cell-invasion and cancer cell-induced angiogenesis. Our work highlights macrophage ability to sustain cancer cell activities as a major concern that needs to be addressed to improve radiotherapy efficacy

Tuberculosis is associated with expansion of a motile, permissive and immunomodulatory CD16(+) monocyte population via the IL-10/STAT3 axis

The human CD14+ monocyte compartment is composed by two subsets based on CD16 expression. We previously reported that this compartment is perturbed in tuberculosis (TB) patients, as reflected by the expansion of CD16+ monocytes along with disease severity. Whether this unbalance is beneficial or detrimental to host defense remains to be elucidated. Here in the context of active TB, we demonstrate that human monocytes are predisposed to differentiate towards an anti-inflammatory (M2-like) macrophage activation program characterized by theCD16+CD163+MerTK+pSTAT3+ phenotype and functional properties such as enhanced protease-dependent motility, pathogen permissivity and immunomodulation. This process is dependent on STAT3 activation, and loss-of-function experiments point towards a detrimental role in host defense against TB. Importantly, we provide a critical correlation between the abundance of the CD16+CD163+MerTK+pSTAT3+ cells and the progression of the disease either at the local level in a non-human primate tuberculous granuloma context, or at the systemic level through the detection of the soluble form of CD163 in human sera. Collectively, this study argues for the pathogenic role of the CD16+CD163+MerTK+pSTAT3+ monocyte-to-macrophage differentiation program and its potential as a target for TB therapy,and promotes the detection of circulating CD163 as a potential biomarker for disease progression and monitoringof treatment efficacy.Fil: Lastrucci, Claire. Centre National de la Recherche Scientifique; FranciaFil: Bénard, Alan. Centre National de la Recherche Scientifique; FranciaFil: Balboa, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Pingris, Karine. Centre National de la Recherche Scientifique; FranciaFil: Souriant, Shanti. Centre National de la Recherche Scientifique; FranciaFil: Poincloux, Renaud. Centre National de la Recherche Scientifique; FranciaFil: Al Saati, Talal. Inserm; FranciaFil: Rasolofo, Voahangy. Pasteur Institute in Antananarivo; MadagascarFil: González Montaner, Pablo. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas ; ArgentinaFil: Inwentarz, Sandra. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas ; ArgentinaFil: Moraña, Eduardo José. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas ; ArgentinaFil: Kondova, Ivanela. Biomedical Primate Research Centre; Países BajosFil: Verreck, Franck A. W.. Biomedical Primate Research Centre; Países BajosFil: Sasiain, María del Carmen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Neyrolles, Olivier. Centre National de la Recherche Scientifique; FranciaFil: Maridonneau Parini, Isabel. Centre National de la Recherche Scientifique; FranciaFil: Lugo Villarino, Geanncarlo. Centre National de la Recherche Scientifique; FranciaFil: Cougoule, Celine. Centre National de la Recherche Scientifique; Franci

miR-155–5p predictive role to decelerate foam cell atherosclerosis through CD36, VAV3, and SOCS1 pathway

MicroRNAs (miRNAs) are noncoding RNA molecules that play a significant role in atherosclerosis pathogenesis through post-transcriptional regulation. In the present work, a bioinformatic analysis using TargetScan and miRdB databases was performed to identify the miRNAs targeting three genes involved in foam cell atherosclerosis (CD36, Vav3, and SOCS1). A total number of three hundred and sixty-seven miRNAs were recognized and only miR-155–5p was selected for further evaluation based on Venn analysis. Another objective of this study was to evaluate the biological process and regulatory network of miR-155–5p associated with foam cell atherosclerosis using DIANA, DAVID, Cytoscape, and STRING tools. Additionally, the comprehensive literature review was performed to prove the miR-155–5p function in foam cell atherosclerosis. miR-155–5p might be related with ox-LDL uptake and endocytosis in macrophage cell by targeting CD36 and Vav3 genes which was showed from the KEGG pathways hsa04979, hsa04666, hsa04145 H, hsa04810, and GO:0099632, GO:0060100, GO:0010743, GO:001745. Furthermore, miR-155–5p was also predicted to increase the cholesterol efflux from macrophage by inhibit SOCS1 expression based on KEGG pathway hsa04120. Eleven original studies were included in the review and strongly suggest the role of miR-155–5p in foam cell atherosclerosis inhibition

Extracellular purine metabolism is the switchboard of immunosuppressive macrophages and a novel target to treat diseases with macrophage imbalances

If misregulated, macrophage (M)T cell interactions can drive chronic inflammation thereby causing diseases, such as rheumatoid arthritis (RA). We report that in a proinflammatory environment, granulocyte-M (GM-CSF)- and M colony-stimulating factor (M-CSF)-dependent Ms have dichotomous effects on T cell activity. While GM-CSF-dependent Ms show a highly stimulatory activity typical for M1 Ms, M-CSF-dependent Ms, marked by folate receptor (FR), adopt an immunosuppressive M2 phenotype. We find the latter to be caused by the purinergic pathway that directs release of extracellular ATP and its conversion to immunosuppressive adenosine by co-expressed CD39 and CD73. Since we observed a misbalance between immunosuppressive and immunostimulatory Ms in human and murine arthritic joints, we devised a new strategy for RA treatment based on targeted delivery of a novel methotrexate (MTX) formulation to the immunosuppressive FR+CD39+CD73+ Ms, which boosts adenosine production and curtails the dominance of proinflammatory Ms. In contrast to untargeted MTX, this approach leads to potent alleviation of inflammation in the murine arthritis model. In conclusion, we define the M extracellular purine metabolism as a novel checkpoint in M cell fate decision-making and an attractive target to control pathological Ms in immune-mediated diseases.The research leading to these results has received funding from the European Union's Horizon 2020 Research and Innovation Program under grant agreement No 683356 - FOLSMART and from the Seventh Framework Program (FP7/2007-2013) under grant agreement NMP4-LA-2009-228827 NANOFOL. RP was supported by the Boehringer Ingelheim Fonds and the Ph.D. program Cell Communication in Health and Disease supported by the Austrian Science Fund (FWF). VL was supported by the FWF (P22908), VEGA (2/0063/14), and APVV (16-0452). JH received support from the Vienna Science and Technology Fund (WWTF) LS14-031.info:eu-repo/semantics/publishedVersio

Datation et caractérisation de processus minéralisateurs à l'Archéen : Application à l'Antimony Line, Ceinture de Roches Vertes de Murchison, Afrique du Sud

Fluid flows through the crust result in the mobilization of elements that can, in turn, generate metal concentrations and the formation of ore bodies. The circulations of such fluids are mainly localized in zones affected by localized deformation, where they modify the chemical composition of the host lithologies. In the Archean Murchison Greenstone Belt (Kaapvaal Craton, South Africa), the Antimony Line is a brittle-ductile structure affected by the circulation of Sb-Au mineralizing fluids. In order to characterize the ore-forming processes, we combined a petro-geochemical study, that focused on stable isotopes and fluid inclusions in particular, with a multi-method dating (U-Th-Pb, Pb-Pb and Ar-Ar) of the ore bodies and their host rocks in and around the Antimony Line. Furthermore, our structural study emphasizes the distributed character of the belt deformation. The Murchison Greenstone Belt experienced a major episode of arc collision and related magmatism at ca 2.97 Ga, contemporaneous with an Au(±Sb) mineralization that may be responsible for a pre-enrichment in Sb. The main Sb mineralization event must be related to the circulation of a metamorphic, H2O-CO2-dominated fluid at 2-3 kbar and 350-450°C. The albitization of the granitoids intrusive into the Antimony Line is dated at 2.8 Ga and is genetically linked to this fluid flow, which took place during the late tectono-metamorphic history of the belt contemporaneously with the emplacement of leucogranites along the southern border of the belt. Therefore, this study further demonstrates that coupling petro-geochemistry and geochronology is a powerful tool in order to study and characterize a given metallogenic system.Les circulations de fluides dans la croûte sont les vecteurs de mobilités élémentaires dont une des conséquences est la concentration de métaux et la genèse de gisements. Ces fluides circulent dans les zones de déformation où ils modifient la composition des roches encaissantes. Dans la ceinture archéenne de roches vertes de Murchison (Afrique du Sud), l'Antimony Line est une zone déformée qui a été le siège de circulations de fluides minéralisateurs en Sb-Au. Pour caractériser les processus minéralisateurs, des données pétro-géochimiques, en particulier en isotopes stables et inclusions fluides, ont été associées à la datation multi-méthode (U-Th-Pb, Pb-Pb et Ar-Ar) des corps minéralisés et de leur encaissant au cœur et autour de l'Antimony Line. L'étude structurale de la région souligne le caractère distribué de la déformation. La ceinture a ainsi subi une phase majeure de collision d'arc, associée à un magmatisme important vers 2.97 Ga, contemporain d'une minéralisation en Au (±Sb) qui pourrait être responsable d'une phase de pré-enrichissement en Sb. La minéralisation principale en Sb est la conséquence de la circulation d'un fluide métamorphique à H2O-CO2, à 2-3 kbar et 350-450°C. L'albitisation de granitoïdes intrusifs dans l'Antimony Line, datée à 2.8 Ga, est génétiquement liée à cette circulation, laquelle s'inscrit donc dans l'histoire tectono-métamorphique tardive de la ceinture et est contemporaine de la mise en place de leucogranites sur la bordure sud. Ces résultats illustrent la pertinence du couplage pétro-géochimie/géochronologie pour la compréhension globale d'un système métallogénique