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Le mésothéliome malin est un cancer rare, généralement causé par une exposition à l’asbeste et affectant les membranes séreuses des cavités pleurales et péritonéales. A l’heure actuelle, les stratégies thérapeutiques restent peu efficaces, engendrant son mauvais pronostic. Les similitudes entre les fibres d’amiante et les nanotubes de carbone (CNT), notamment leur capacité à induire le mésothéliome, rendent l’utilisation de ce matériau préoccupante pour la santé publique. Des recherches expérimentales sont donc nécessaires pour mieux comprendre les mécanismes pathogéniques menant au mésothéliome induit par les fibres d’amiante et les nanotubes de carbone. Notre projet a pour but de caractériser les réponses immunosuppressives lors du développement di mésothéliome chez le rat traité aux CNT. Il est maintenant connu que des cellules immunosuppressive sont présentes dans le microenvironnement tumoral ; elles inhibent l’immunité innée et adaptative, déstabilisent la surveillance immunitaire et empêchent les réponses immunitaires anti-tumorales. Nous déterminons en particulier si les réponses cancérigènes précoces aux CNT Mitsui-7 (CNT-7) sont associées à l’accumulation de macrophages immunosuppresseurs. Nous utilisons un modèle péritonéal chez le rat Wistar qui permet d’exposer directement les cellules mésothéliales aux CNT ou à l’asbeste, et de prélever facilement des échantillons de la cavité séreuse afin d’évaluer les réponses macrophagiques durant le processus cancérigène. Nous avons confirmé que les macrophages CD11b/c high et his48int présents dans le microenvironnement du mésothéliome induit par les CNT-7 et triés par FACS ont la capacité d’inhiber l’activation polyclonale des lymphocytes T in vitro. Ces macrophages suppresseurs sont déjà présents, grâce à une prolifération locale, lors de la réponse précoce aux CNT cancérigènes ou à l’asbeste (jour 1 à 30) , bien avant le développement du mésothéliome (6 mois). Ces cellules accumulées de manière précoces n’ont pas été observés chez la souris, résistante au mésothéliome induit par les CNT-7. L’analyse de l’expression des gènes immunosuppresseurs (RT-qPCR) a révélé que les macrophages péritonéaux de rats traités aux CNT (jour 1 à 30) expriment fortement les médiateurs immunosuppresseurs IL-10 et Arginase-1, comparativement aux macrophages péritonéaux naïfs ou aux macrophages obtenus après traitement à la silice, une particule n’induisant pas le mésothéliome. Dès lors nos données indiquent que les nanotubes cancérigènes possèdent la capacité d’induire une accumulation préférentielle, rapide et soutenue de macrophages immunosuppresseurs avant que le mésothéliome ne soit établi. Cette accumulation de macrophages immunosuppresseurs lors du développement du mésothéliome supporte l’utilisation des réponses immunosuppressives pour détecter les nanomatériaux mésothéliomagéniques. MM is a rare cancer caused by asbestos exposure affecting the serous membrane of pleural and peritoneal cavities. MM remains a highly refractory cancer to existing therapeutic strategies. The asbestos-like toxicity of engineered carbon nanotubes (CNT). Notably their capacity to induce malignant mesothelioma (MM), is a serious cause of concern for public health. Intensive research efforts are therefore needed to better understand the pathomechanisms of CNT-induced MM. The present project deals with immunosuppression during the mesothelial response to CNT in rats. There is growing evidence that tumors harbor immunosuppressive cells that inhibit both innate and adaptive immunity, subverting immune surveillance and preventing efficient natural or therapeutic anti-tumor immune responses. We aim to determine if the carcinogenic response to Mitsio-7 CNT (CNT-7) is associated with accumulation of immunosuppressive macrophages. We used a Wistar rat peritoneum model which allows directly exposing mesothelial cells to CNT or asbestos, and easily sampling the mesothelial cavity for monitoring macrophage responses during the carcinogenic process. We show that FACS-sorted CD11b/c high and His48int macrophages present in CNT-7 induced mesothelioma microenvironment suppress polyclonal activation of T lymphocytes in vitro. The inhibitory macrophages are already present during the early response to carcinogenic CNT or asbestos (day 1 to 30), well before the establishment of mesothelioma (6 months). Immunosuppressive peritoneal macrophages were not observed in mice, which are resistant to mesothelioma development upon CNT-7. RTqPCR revealed that peritoneal macrophages purified from CNT-treated rats (day 1-30) highly expressed the immunosuppressive mediators IL-10 and Arginase-1 in comparison to naïve peritoneal macrophages or macrophages obtained after silica, a particle that does not induce mesothelioma. Altogether, our data demonstrate that carcinogenic CNT possess the intrinsic capacity to induce a preferential, rapid and sustained accumulation of immunosuppressive macrophages before mesothelioma is established. These data provide new insight into the possible contribution of immunosuppression in the early pathogenic processes of CNT-induced mesothelioma.

Macrophages --- Mesothelioma

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The mononuclear phagocyte system (MPS) comprises dendritic cells (DCs), monocytes and macrophages (MØs) that together play crucial roles in tissue immunity and homeostasis, but also contribute to a broad spectrum of pathologies. They are thus attractive therapeutic targets for immune therapy. However, the distinction between DCs, monocytes and MØ subpopulations has been a matter of controversy and the current nomenclature has been a confounding factor. DCs are remarkably heterogeneous and consist of multiple subsets traditionally defined by their expression of various surface markers. While markers are important to define various populations of the MPS, they do not specifically define the intrinsic nature of a cell population and do not always segregate a bona fide cell type of relative homogeneity. Markers are redundant, or simply define distinct activation states within one subset rather than independent subpopulations. One example are the steady-state CD11b+ DCs which are often not distinguished from monocytes, monocyte-derived cells, and macrophages due to their overlapping phenotype. Lastly, monocyte fate during inflammation results in cells bearing the phenotypic and functional features of both DCs and MØs significantly adding to the confusion. In fact, depending on the context of the study and the focus of the laboratory, a monocyte-derived cell will be either be called "monocyte-derived DCs" or "macrophages". Because the names we give to cells are often associated with a functional connotation, this is much more than simple semantics. The "name" we give to a population fundamentally changes the perception of its biology and can impact on research design and interpretation. Recent evidence in the ontogeny and transcriptional regulation of DCs and MØs, combined with the identification of DC- and MØ-specific markers has dramatically changed our understanding of their interrelationship in the steady state and inflammation. In steady state, DCs are constantly replaced by circulating blood precursors that arise from committed progenitors in the bone marrow. Similarly, some MØ populations are also constantly replaced by circulating blood monocytes. However, others tissue MØs are derived from embryonic precursors, are seeded before birth and maintain themselves in adults by self-renewal. In inflammation, such differentiation pathways are fundamentally changed and unique monocyte-derived inflammatory cells are generated. Current DC, monocyte and MØ nomenclature does not take into account these new developments and as a consequence is quite confusing. We believe that the field is in need of a fresh view on this topic as well as an upfront debate on DC and MØ nomenclature. Our aim is to bring expert junior and senior scientists to revisit this topic in light of these recent developments. This Research Topic will cover all aspects of DC, monocyte and MØ biology including development, transcriptional regulation, functional specializations, in lymphoid and non-lymphoid tissues, and in both human and mouse models. Given the central position of DCs, monocytes and MØs in tissue homeostasis, immunity and disease, this topic should be of interest to a large spectrum of the biomedical community.

Dendritic cells --- Macrophages --- nomenclature --- Monocytes --- development --- Dendritic Cells --- Subset --- differentiation --- Antigen Presentation --- Mononuclear Phagocyte System --- Ontogeny --- Macrophages --- Nomenclature. --- Nomenclature. --- nomenclature --- Monocytes --- development --- Dendritic Cells --- Subset --- differentiation --- Antigen Presentation --- Mononuclear Phagocyte System --- Ontogeny --- Macrophages

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The mononuclear phagocyte system (MPS) comprises dendritic cells (DCs), monocytes and macrophages (MØs) that together play crucial roles in tissue immunity and homeostasis, but also contribute to a broad spectrum of pathologies. They are thus attractive therapeutic targets for immune therapy. However, the distinction between DCs, monocytes and MØ subpopulations has been a matter of controversy and the current nomenclature has been a confounding factor. DCs are remarkably heterogeneous and consist of multiple subsets traditionally defined by their expression of various surface markers. While markers are important to define various populations of the MPS, they do not specifically define the intrinsic nature of a cell population and do not always segregate a bona fide cell type of relative homogeneity. Markers are redundant, or simply define distinct activation states within one subset rather than independent subpopulations. One example are the steady-state CD11b+ DCs which are often not distinguished from monocytes, monocyte-derived cells, and macrophages due to their overlapping phenotype. Lastly, monocyte fate during inflammation results in cells bearing the phenotypic and functional features of both DCs and MØs significantly adding to the confusion. In fact, depending on the context of the study and the focus of the laboratory, a monocyte-derived cell will be either be called "monocyte-derived DCs" or "macrophages". Because the names we give to cells are often associated with a functional connotation, this is much more than simple semantics. The "name" we give to a population fundamentally changes the perception of its biology and can impact on research design and interpretation. Recent evidence in the ontogeny and transcriptional regulation of DCs and MØs, combined with the identification of DC- and MØ-specific markers has dramatically changed our understanding of their interrelationship in the steady state and inflammation. In steady state, DCs are constantly replaced by circulating blood precursors that arise from committed progenitors in the bone marrow. Similarly, some MØ populations are also constantly replaced by circulating blood monocytes. However, others tissue MØs are derived from embryonic precursors, are seeded before birth and maintain themselves in adults by self-renewal. In inflammation, such differentiation pathways are fundamentally changed and unique monocyte-derived inflammatory cells are generated. Current DC, monocyte and MØ nomenclature does not take into account these new developments and as a consequence is quite confusing. We believe that the field is in need of a fresh view on this topic as well as an upfront debate on DC and MØ nomenclature. Our aim is to bring expert junior and senior scientists to revisit this topic in light of these recent developments. This Research Topic will cover all aspects of DC, monocyte and MØ biology including development, transcriptional regulation, functional specializations, in lymphoid and non-lymphoid tissues, and in both human and mouse models. Given the central position of DCs, monocytes and MØs in tissue homeostasis, immunity and disease, this topic should be of interest to a large spectrum of the biomedical community.

Dendritic cells --- Macrophages --- Nomenclature. --- nomenclature --- Monocytes --- development --- Dendritic Cells --- Subset --- differentiation --- Antigen Presentation --- Mononuclear Phagocyte System --- Ontogeny