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1. Eye Lens Organoids Made Simple: Characterization of a New Three-Dimensional Organoid Model for Lens Development and Pathology

Author

Matthieu Duot, Roselyne Viel, Justine Viet, Catherine Le Goff-Gaillard, Luc Paillard, Salil A. Lachke, Carole Gautier-Courteille, and David Reboutier

Subjects
cataract, eye lens, organoid, pathophysiology, Celf1, Cytology, QH573-671
Abstract

Cataract, the opacification of the lens, is the leading cause of blindness worldwide. Although effective, cataract surgery is costly and can lead to complications. Toward identifying alternate treatments, it is imperative to develop organoid models relevant for lens studies and drug screening. Here, we demonstrate that by culturing mouse lens epithelial cells under defined three-dimensional (3D) culture conditions, it is possible to generate organoids that display optical properties and recapitulate many aspects of lens organization and biology. These organoids can be rapidly produced in large amounts. High-throughput RNA sequencing (RNA-seq) on specific organoid regions isolated via laser capture microdissection (LCM) and immunofluorescence assays demonstrate that these lens organoids display a spatiotemporal expression of key lens genes, e.g., Jag1, Pax6, Prox1, Hsf4 and Cryab. Further, these lens organoids are amenable to the induction of opacities. Finally, the knockdown of a cataract-linked RNA-binding protein encoding gene, Celf1, induces opacities in these organoids, indicating their use in rapidly screening for genes that are functionally relevant to lens biology and cataract. In sum, this lens organoid model represents a compelling new tool to advance the understanding of lens biology and pathology and can find future use in the rapid screening of compounds aimed at preventing and/or treating cataracts.

Published
2023
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2. Dietary Protein Intake Level Modulates Mucosal Healing and Mucosa-Adherent Microbiota in Mouse Model of Colitis

Author

Sandra Vidal-Lletjós, Mireille Andriamihaja, Anne Blais, Marta Grauso, Patricia Lepage, Anne-Marie Davila, Roselyne Viel, Claire Gaudichon, Marion Leclerc, François Blachier, and Annaïg Lan

Subjects
dietary protein level, colitis, epithelial repair, mucosa-adherent microbiota, Nutrition. Foods and food supply, TX341-641
Abstract

Mucosal healing after an inflammatory flare is associated with lasting clinical remission. The aim of the present work was to evaluate the impact of the amount of dietary protein on epithelial repair after an acute inflammatory episode. C57BL/6 DSS-treated mice received isocaloric diets with different levels of dietary protein: 14% (P14), 30% (P30) and 53% (P53) for 3 (day 10), 6 (day 13) and 21 (day 28) days after the time of colitis maximal intensity. While the P53 diet worsened the DSS- induced inflammation both in intensity and duration, the P30 diet, when compared to the P14 diet, showed a beneficial effect during the epithelial repair process by accelerating inflammation resolution, reducing colonic permeability and increasing epithelial repair together with epithelial hyperproliferation. Dietary protein intake also impacted mucosa-adherent microbiota composition after inflammation since P30 fed mice showed increased colonization of butyrate-producing genera throughout the resolution phase. This study revealed that in our colitis model, the amount of protein in the diet modulated mucosal healing, with beneficial effects of a moderately high-protein diet, while very high-protein diet displayed deleterious effects on this process.

Published
2019
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3. Hepatocellular carcinomas, exhibiting intratumor fibrosis, express cancer-specific extracellular matrix remodeling and WNT/TGFB signatures, associated with poor outcome

Author

Romain Desert, Wei Chen, Xiaodong Ge, Roselyne Viel, Hui Han, Dipti Athavale, Sukanta Das, Zhuolun Song, Daniel Lantvit, Luis Cano, Alexandra Naba, Orlando Musso, Natalia Nieto, University of Illinois [Chicago] (UIC), University of Illinois System, H2P2 - Histo Pathologie Hight Precision (H2P2), and Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
Hepatology, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology
Abstract

International audience; BACKGROUND AIMS: Hepatocellular carcinoma (HCC), the third cause of cancer-related death, arises in the context of liver fibrosis (LF). Although HCC is generally poorly fibrogenic, some tumors harbor focal intratumor extracellular matrix (ECM) deposits, called fibrous nests. To date, the molecular composition and the clinical relevance of these ECM deposits has not been fully defined. APPROACH RESULTS: We performed quantitative matrisome analysis by tandem mass tags mass spectrometry (TMT-MS) in 20 human HCCs, with high- or low-grade intratumor fibrosis, and matched non-tumor (NT) tissues, as well as in 12 livers from mice treated with vehicle, CCl4 or diethylnitrosamine (DEN). We found 94 ECM proteins differentially abundant between high- and low-grade fibrous nests, including interstitial and basement membrane components, such as several collagens, glycoproteins, proteoglycans, enzymes involved in ECM stabilization and degradation, and growth factors. Pathway analysis revealed a metabolic switch in high-grade fibrosis, with enhanced glycolysis and decreased oxidative phosphorylation. Integrating our quantitative proteomics data with the transcriptomes from HCCs and NT livers (n = 2,285 samples), we identified a subgroup of fibrous nest HCCs, characterized by cancer-specific ECM remodeling, expression of the WNT/TGFB (S1) subclass signature, and poor patient outcome. Fibrous nest HCCs, abundantly expressed an 11 fibrous nest proteins’ signature, associated with poor patient outcome, by multivariate Cox analysis, and validated by multiplex immunohistochemistry. CONCLUSION: Matrisome analysis highlighted cancer-specific ECM deposits, typical of the WNT/TGFB HCC subclass, associated with poor patient outcome. Hence, histological reporting of intratumor fibrosis in HCC is of clinical relevance.

Published
2023

4. The mechanosensitive <scp>TRPV2</scp> calcium channel promotes human melanoma invasiveness and metastatic potential

Author

Kenji F Shoji, Elsa Bayet, Sabrina Leverrier‐Penna, Dahiana Le Devedec, Aude Mallavialle, Séverine Marionneau‐Lambot, Florian Rambow, Raul Perret, Aurélie Joussaume, Roselyne Viel, Alain Fautrel, Amir Khammari, Bruno Constantin, Sophie Tartare‐Deckert, Aubin Penna, Pecqueret, Valérie, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Canaux et Connexines dans les Cancers et Cellules Souches (4CS), Université de Poitiers-Centre National de la Recherche Scientifique (CNRS), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Cancéropôle Grand-Ouest [Bretagne-Centre-Pays de Loire], Universität Duisburg-Essen [Essen], West German Cancer Center [Essen, Germany], Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Immunology and New Concepts in ImmunoTherapy (INCIT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Biosit : biologie, santé, innovation technologique (SFR UMS CNRS 3480 - INSERM 018), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), ANR‐12‐JSV2‐0004‐001, Agence Nationale de la Recherche, PJA20151203419, Fondation ARC pour la Recherche sur le Cancer, Ligue Contre le Cancer, Université de Rennes 1, and Universität Duisburg-Essen = University of Duisburg-Essen [Essen]

Subjects
[SDV] Life Sciences [q-bio], migration, [SDV]Life Sciences [q-bio], Medizin, melanoma, Genetics, metastasis, calpain, Molecular Biology, Biochemistry, TRPV2 channel
Abstract

Melanoma is a highly aggressive cancer endowed with a unique capacity of rapidly metastasizing, which is fundamentally driven by aberrant cell motility behaviors. Discovering "migrastatics" targets, specifically controlling invasion and dissemination of melanoma cells during metastasis, is therefore of primary importance. Here, we uncover the prominent expression of the plasma membrane TRPV2 calcium channel as a distinctive feature of melanoma tumors, directly related to melanoma metastatic dissemination. In vitro as well as in vivo, TRPV2 activity is sufficient to confer both migratory and invasive potentials, while conversely TRPV2 silencing in highly metastatic melanoma cells prevents aggressive behavior. In invasive melanoma cells, TRPV2 channel localizes at the leading edge, in dynamic nascent adhesions, and regulates calcium-mediated activation of calpain and the ensuing cleavage of the adhesive protein talin, along with F-actin organization. In human melanoma tissues, TRPV2 overexpression correlates with advanced malignancy and poor prognosis, evoking a biomarker potential. Hence, by regulating adhesion and motility, the mechanosensitive TRPV2 channel controls melanoma cell invasiveness, highlighting a new therapeutic option for migrastatics in the treatment of metastatic melanoma. ispartof: EMBO REPORTS vol:24 issue:4 ispartof: location:England status: published

Published
2023

5. TNF-α and IL-10 Control CXCL13 Expression in Human Macrophages

Author

Laurent Vernhet, Francisco Llamas-Gutierrez, Stéphane Jouneau, Valérie Lecureur, Audrey Joannes, Roselyne Viel, Lutz Wollin, Nessrine Bellamri, Bertrand De Latour, Claudie Morzadec, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), H2P2 - Histo Pathologie Hight Precision (H2P2), Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Boehringer Ingelheim Pharma GmbH & Co. KG, Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), and Jonchère, Laurent

Subjects
Male, Chemokine, [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV]Life Sciences [q-bio], Immunology, Gene Expression, Neogenesis, stat, 03 medical and health sciences, Idiopathic pulmonary fibrosis, 0302 clinical medicine, Macrophages, Alveolar, Humans, Immunology and Allergy, Medicine, CXCL13, Lung, Aged, Janus Kinases, 030304 developmental biology, 0303 health sciences, biology, Tumor Necrosis Factor-alpha, business.industry, CD68, Macrophages, NF-kappa B, Interstitial lung disease, respiratory system, biology.organism_classification, medicine.disease, Chemokine CXCL13, Idiopathic Pulmonary Fibrosis, Interleukin-10, respiratory tract diseases, 3. Good health, [SDV] Life Sciences [q-bio], STAT Transcription Factors, Interleukin 10, biology.protein, Cancer research, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Lung Diseases, Interstitial, business, Signal Transduction, 030215 immunology
Abstract

The chemokine CXCL13 controls the normal organization of secondary lymphoid tissues and the neogenesis of ectopic lymphoid structures in nonlymphoid organs, particularly the lungs. The progression and severity of idiopathic pulmonary fibrosis (IPF), a fatal and irreversible interstitial lung disease, is predicted by the circulating blood concentrations of CXCL13. Although CXCL13 is produced by pulmonary tissues, it has not been determined which cells are involved. This study examines CXCL13 production by lung tissue macrophages from patients with IPF and the signaling pathways controlling CXCL13 gene expression in human alveolar macrophages (AM) and monocyte-derived macrophages (MoDM). CXCL13 is found in CD68- and CD206-positive AM from patients with IPF, and the CXCL13 gene is induced in these macrophages and MoDM when they are stimulated with LPS. We found that TNF-α and IL-10 control optimal CXCL13 gene expression in MoDM and possibly in AM by activating the NF-κB and JAK/STAT pathways, respectively. We also found that blood TNF-α and CXCL13 concentrations are significantly correlated in patients with IPF, suggesting that TNF-α contributes to CXCL13 production in humans. In conclusion, the results of this study demonstrate that AM from patients with IPF produces CXCL13 and that the NF-κB and JAK/STAT pathways are required to induce the expression of this major chemokine.

Published
2020

6. An EMT–primary cilium–GLIS2 signaling axis regulates mammogenesis and claudin-low breast tumorigenesis

Author

Vincent J Guen, Jane E. Visvader, Qiong Ding, Philippe Juin, Matthieu Le Gallo, Anton M. Jetten, Tony E. Chavarria, Claude Prigent, Sophie G. Martin, Hong Soon Kang, Massimo Attanasio, Amandine Salamagnon, Patrick Tas, Arjun Bhutkar, Florence Godey, Roselyne Viel, Molly M. Wilson, Jacqueline A. Lees, Céline Callens, Svetlana Mironov, Robert A. Weinberg, Abena D. Peasah, Jonchère, Laurent, Massachusetts Institute of Technology (MIT), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Carver College of Medicine, University of Iowa, H2P2 - Histo Pathologie Hight Precision (H2P2), Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CRLCC Eugène Marquis (CRLCC), National Institute of Environmental Health Sciences [Durham] (NIEHS-NIH), National Institutes of Health [Bethesda] (NIH), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), University of Melbourne, Centre de recherche en Biologie cellulaire de Montpellier (CRBM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the MIT Stem Cell Initiative through Fondation MIT, Koch Institute Support (core) grant P30-CA14051 from the National Cancer Institute, Fondation ARC, Cancéropôle Grand Ouest, Université de Rennes 1, SIRIC ILIAD, and Fondation de France. M.M.W. was supported by the David H. Koch Graduate Fellowship. A.M.J. research was supported by the Intramural Research Program of the NIEHS, NIH Z01-ES-101585. V.J.G. was supported by Postdoctoral Fellowships from the Koch Institute and Fondation ARC., Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Centre de recherche en Biologie Cellulaire (CRBM), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), and Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Ciliogenesis, medicine, Transcription factor, ComputingMilieux_MISCELLANEOUS, Cancer, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, Multidisciplinary, Fibroblast growth factor receptor 1, Cilium, SciAdv r-articles, Cell Biology, Claudin-Low, Cell biology, 030220 oncology & carcinogenesis, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Biomedicine and Life Sciences, Stem cell, Carcinogenesis, Ciliary base, Research Article
Abstract

Description, EMT induces cilium assembly and signaling to promote mammogenesis and tumorigenesis., The epithelial-mesenchymal transition (EMT) and primary ciliogenesis induce stem cell properties in basal mammary stem cells (MaSCs) to promote mammogenesis, but the underlying mechanisms remain incompletely understood. Here, we show that EMT transcription factors promote ciliogenesis upon entry into intermediate EMT states by activating ciliogenesis inducers, including FGFR1. The resulting primary cilia promote ubiquitination and inactivation of a transcriptional repressor, GLIS2, which localizes to the ciliary base. We show that GLIS2 inactivation promotes MaSC stemness, and GLIS2 is required for normal mammary gland development. Moreover, GLIS2 inactivation is required to induce the proliferative and tumorigenic capacities of the mammary tumor–initiating cells (MaTICs) of claudin-low breast cancers. Claudin-low breast tumors can be segregated from other breast tumor subtypes based on a GLIS2-dependent gene expression signature. Collectively, our findings establish molecular mechanisms by which EMT programs induce ciliogenesis to control MaSC and MaTIC stemness, mammary gland development, and claudin-low breast cancer formation.

Published
2021

7. The mechanosensitive TRPV2 calcium channel controls human melanoma invasiveness and metastatic potential

Author

Elsa Bayet, Aurélie Joussaume, Amir Khammari, Raul Perret, Aude Mallavialle, Bruno Constantin, Florian Rambow, Alain Fautrel, Roselyne Viel, Sophie Tartare-Deckert, Sabrina Leverrier-Penna, Séverine Marionneau-Lambot, Dahiana Le Devedec, Aubin Penna, Kenji F. Shoji, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Signalisation et Transports Ioniques Membranaires (STIM), Université de Poitiers-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Cancéropôle Grand-Ouest [Bretagne-Centre-Pays de Loire], Leuven Center for Cancer Biology (VIB-KU-CCB), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven)-Vlaams Instituut voor Biotechnologie [Ghent, Belgique] (VIB), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), H2P2 - Histo Pathologie Hight Precision (H2P2), Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Clinical and Translational Research in Skin Cancer (CRCINA-ÉQUIPE 2), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de dermatologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), and PENNA, Aubin

Subjects
Calcium channel, Melanoma, TRPV2, Regulator, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, medicine.disease, Metastasis, Focal adhesion, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Cancer research, Gene silencing, Mechanosensitive channels
Abstract

Discovery of therapeutic targets against metastasis is of primary importance since being the main cause of cancer-related death. Melanoma is a highly aggressive cancer endowed with a unique capacity of rapidly metastasizing. Deregulation of calcium homeostasis has been involved in numerous cellular metastatic behaviors, although the molecular determinants supporting these processes often remain unclear. Here, we evidenced a prominent expression of the plasma membrane TRPV2 calcium channel as a distinctive feature of melanoma tumors, directly related to melanoma metastatic progression and dissemination. In vitro as well as in vivo, TRPV2 activity was sufficient to confer both migratory and invasive phenotypes to non-invasive melanoma cells, while conversely upon TRPV2 silencing, highly metastatic melanoma cells failed to retain their malignant behaviors. We established a model whereupon activation of the mechanosensitive TRPV2 channel, localized in highly dynamic nascent adhesion clusters, directly regulates calpain-dependent cleavage of the adhesive protein talin together with F-actin network. By operating at the crossroad of the tumor microenvironment and the intracellular machinery, mechanosensitive TRPV2 channel controls melanoma cells aggressiveness. Finally in human melanoma tumor samples, TRPV2 overexpression represents a molecular marker of advanced malignancy and bad prognosis, highlighting a new therapeutic option for migrastatics in the treatment of metastatic melanoma.SignificanceOne essential feature of metastatic cells is enhanced motility and invasiveness. This study evidences TRPV2 channel control over metastatic melanoma invasiveness, highlights new migration regulatory mechanisms, and reveals this channel as a biomarker and migrastatic target for the treatment of advanced melanoma.

Published
2021

8. PIM2 kinase has a pivotal role in plasmablast generation and plasma cell survival, opening up novel treatment options in myeloma

Author

Marion Haas, Gersende Caron, Fabrice Chatonnet, Stéphane Manenti, Elina Alaterre, Julie Devin, Céline Delaloy, Giulia Bertolin, Roselyne Viel, Amandine Pignarre, Francisco Llamas-Gutierrez, Anne Marchalot, Olivier Decaux, Karin Tarte, Laurent Delpy, Jérôme Moreaux, and Thierry Fest

Subjects
Cell Survival, Cell Line, Tumor, Proto-Oncogene Proteins, Immunology, Plasma Cells, Humans, Apoptosis, Cell Biology, Hematology, Protein Serine-Threonine Kinases, Multiple Myeloma, Biochemistry, humanities
Abstract

The differentiation of B cells into plasmablasts (PBs) and then plasma cells (PCs) is associated with extensive cell reprogramming and new cell functions. By using specific inhibition strategies (including a novel morpholino RNA antisense approach), we found that early, sustained upregulation of the proviral integrations of Moloney virus 2 (PIM2) kinase is a pivotal event during human B-cell in vitro differentiation and then continues in mature normal and malignant PCs in the bone marrow. In particular, PIM2 sustained the G1/S transition by acting on CDC25A and p27Kip1 and hindering caspase 3–driven apoptosis through BAD phosphorylation and cytoplasmic stabilization of p21Cip1. In PCs, interleukin-6 triggered PIM2 expression, resulting in antiapoptotic effects on which malignant PCs were particularly dependent. In multiple myeloma, pan-PIM and myeloid cell leukemia-1 (MCL1) inhibitors displayed synergistic activity. Our results highlight a cell-autonomous function that links kinase activity to the newly acquired secretion ability of the PBs and the adaptability observed in both normal and malignant PCs. These findings should finally prompt the reconsideration of PIM2 as a therapeutic target in multiple myeloma.

Published
2021

9. Exposure of human fetal kidneys to mild analgesics interferes with early nephrogenesis

Author

Christèle Desdoits-Lethimonier, Alain Michel, Antonio Suglia, Cécile Vigneau, Laetitia L Lecante, Roselyne Viel, Vincent Lavoué, Antoine Rolland, Jonathan Maurice Chemouny, Nathalie Dejucq-Rainsford, Emmanuelle Becker, Sabrina Leverrier-Penna, Séverine Mazaud-Guittot, Hugoline Boulay, Nathalie Costet, Signalisation et Transports Ioniques Membranaires (STIM), Université de Poitiers-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), École des Hautes Études en Santé Publique [EHESP] (EHESP), CHU Pontchaillou [Rennes], Biosit : biologie, santé, innovation technologique (SFR UMS CNRS 3480 - INSERM 018), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), H2P2 - Histo Pathologie Hight Precision (H2P2), Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut National de la Santé et de la Recherche Médicale (Inserm), Université de Rennes 1 (University of Rennes 1), Ecole des Hautes Etudes en Santé Publique, Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM). Grant Number: HAP-2014-073, Agence Nationale de la Recherche (ANR). Grant Number: ANR-15-CE34-0001-01, Société de Néphrologie (French Society of Nephrology), ANR-15-CE34-0001,ACETAMINOV,Antalgiques et différenciation ovarienne fœtale chez l'Homme(2015), Université de Poitiers-Université de Tours-Centre National de la Recherche Scientifique (CNRS), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)

Subjects
0301 basic medicine, NSAIDs, Organogenesis, [SDV]Life Sciences [q-bio], Kidney Glomerulus, Physiology, Prostaglandin, nephrogenesis, Biochemistry, Fetal Kidney, Nephrotoxicity, prostaglandins, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Fetus, Pregnancy, Genetics, Medicine, Humans, fetal kidney, Molecular Biology, acetaminophen, Kidney, Aspirin, Analgesics, Cell Death, business.industry, Ibuprofen, 3. Good health, Acetaminophen, Pregnancy Trimester, First, 030104 developmental biology, medicine.anatomical_structure, chemistry, Female, business, 030217 neurology & neurosurgery, Ex vivo, Biotechnology, medicine.drug
Abstract

International audience; Acetaminophen, aspirin, and ibuprofen are mild analgesics commonly used by pregnant women, the sole current recommendation being to avoid ibuprofen from the fifth month of gestation. The nephrotoxicity of these three analgesics is well documented in adults, as is their interference with prostaglandins biosynthesis. Here we investigated the effect of these analgesics on human first trimester kidneys ex vivo. We first evaluated prostaglandins biosynthesis functionality by performing a wide screening of prostaglandin expression patterns in first trimester human kidneys. We demonstrated that prostaglandins biosynthesis machinery is functional during early nephrogenesis. Human fetal kidney explants aged 7-12 developmental weeks were exposed ex vivo to ibuprofen, aspirin or acetaminophen for 7 days, and analyzed by histology, immunohistochemistry, and flow cytometry. This study has revealed that these analgesics induced a spectrum of abnormalities within early developing structures, ranging from cell death to a decline in differentiating glomeruli density. These results warrant caution for the use of these medicines during the first trimester of pregnancy.

Published
2021

10. Implication of nigral dopaminergic lesion and repeated L-dopa exposure in neuropsychiatric symptoms of Parkinson’s disease

Author

Bertrand Rion, Roselyne Viel, Anne-Sophie Denibaud, Simon Loiodice, Pierre Montagne, Harry Wing Young, Benoît Méot, Christophe Drieu La Rochelle, Biotrial, H2P2 - Histo Pathologie Hight Precision (H2P2), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
Male, Parkinson's disease, Dopamine, [SDV]Life Sciences [q-bio], Anxiety, Antiparkinson Agents, Levodopa, Rats, Sprague-Dawley, Behavioral Neuroscience, Benserazide, 0302 clinical medicine, Forelimb, L-dopa, 0303 health sciences, Dopaminergic, Substantia Nigra, medicine.symptom, Locomotion, medicine.drug, medicine.medical_specialty, Elevated plus maze, Tyrosine 3-Monooxygenase, Context (language use), Substantia nigra, 6-OHDA, Lesion, 03 medical and health sciences, Internal medicine, medicine, Animals, Interpersonal Relations, Parkinson Disease, Secondary, Maze Learning, Oxidopamine, Gait Disorders, Neurologic, 030304 developmental biology, Memory Disorders, business.industry, Pars compacta, Recognition, Psychology, medicine.disease, Rats, Amphetamine, Disease Models, Animal, Endocrinology, Sympatholytics, Parkinson’s disease, neuropsychiatric symptoms, business, 030217 neurology & neurosurgery
Abstract

This study aims to investigate the contribution of nigral dopaminergic (DA) cell loss, repeated exposure to DA medication and the combination of both to the development of neuropsychiatric symptoms observed in Parkinson’s disease (PD). A bilateral 6-OHDA lesion of the substantia nigra pars compacta (SNc) was performed in rats. A set of animals was repeatedly administered with L -dopa (20 mg/kg/day) and benserazide (5 mg/kg/day) over 10 days starting from day 11 post-lesion. Behavioural testing was performed in week 3 post-lesion: novel object recognition (NOR), elevated plus maze (EPM) social interaction (SI) tests, and amphetamine-induced hyperlocomotion (AIH). Immunohistochemical analysis revealed a significant partial lesion (48%) in 6-OHDA versus sham rats. This lesion was not associated with motor impairment. However, lesioned rats displayed a significant deficit in the NOR, which was reversed by acute treatment with l -dopa/benserazide (12.5 mg/kg and 15 mg/kg respectively). Lesioned rats also displayed a deficit in the EPM which was not reversed by acute treatment with l -dopa. No difference was observed in the SI test or in the AIH assay. In all assays, no effect of chronic l -dopa exposure was observed. This study provides new insights into the neuropathophysiology associated with neuropsychiatric symptoms of PD. Our data strongly emphasises a not previously clearly identified critical role in cognition for the SNc. The results suggest that DA pathways were less directly involved in lesion-induced anxiety-like behaviour. We did not report any effect of chronic l -dopa exposure in the context of partial nigral cell loss.

Published
2019

11. Dietary Protein Intake Level Modulates Mucosal Healing and Mucosa-Adherent Microbiota in Mouse Model of Colitis

Author

Marta Grauso, Patricia Lepage, Roselyne Viel, Marion Leclerc, François Blachier, Mireille Andriamihaja, Claire Gaudichon, Sandra Vidal-Lletjós, Annaïg Lan, Anne Blais, Anne-Marie Davila, Physiologie de la Nutrition et du Comportement Alimentaire (PNCA), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), H2P2 - Histo Pathologie Hight Precision (H2P2), Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut National de Recherche Agronomique - AgroParisTech, Societe Francaise de Nutrition, Association Francois Aupetit, INRA-Universite Paris-Saclay (ALIAS program), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and AgroParisTech-Institut National de la Recherche Agronomique (INRA)

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, colitis, [SDV]Life Sciences [q-bio], epithelial repair, Inflammation, lcsh:TX341-641, Article, Mice, 03 medical and health sciences, 0302 clinical medicine, Inflammation resolution, dietary protein level, mucosa-adherent microbiota, Internal medicine, Animals, Medicine, Intestinal Mucosa, Colitis, Beneficial effects, 2. Zero hunger, 030109 nutrition & dietetics, Nutrition and Dietetics, business.industry, medicine.disease, Animal Feed, Diet, Gastrointestinal Microbiome, 3. Good health, Mice, Inbred C57BL, Disease Models, Animal, Dietary protein, Endocrinology, Mucosal healing, 030211 gastroenterology & hepatology, Dietary Proteins, medicine.symptom, business, lcsh:Nutrition. Foods and food supply, Dietary protein intake, Microbiota composition, Food Science
Abstract

International audience; Mucosal healing after an inflammatory flare is associated with lasting clinical remission. The aim of the present work was to evaluate the impact of the amount of dietary protein on epithelial repair after an acute inflammatory episode. C57BL/6 DSS-treated mice received isocaloric diets with different levels of dietary protein 14% (P14), 30% (P30) and 53% (P53) for 3 (day 10), 6 (day 13) and 21 (day 28) days after the time of colitis maximal intensity. While the P53 diet worsened the DSS- induced inflammation both in intensity and duration, the P30 diet, when compared to the P14 diet, showed a beneficial effect during the epithelial repair process by accelerating inflammation resolution, reducing colonic permeability and increasing epithelial repair together with epithelial hyperproliferation. Dietary protein intake also impacted mucosa-adherent microbiota composition after inflammation since P30 fed mice showed increased colonization of butyrate-producing genera throughout the resolution phase. This study revealed that in our colitis model, the amount of protein in the diet modulated mucosal healing, with beneficial effects of a moderately high-protein diet, while very high-protein diet displayed deleterious effects on this process.

Published
2019

12. Thymoquinone protects rat liver after partial hepatectomy under ischemia/reperfusion through oxidative stress and endoplasmic reticulum stress prevention

Author

Najet Hadj Abdallah, Anne Corlu, Mohamed Bejaoui, Hassen Ben Abdennebi, Catherine Ribault, Ahlem Bouhlel, Hassen Hentati, Ismail Ben Mosbah, Roselyne Viel, Université de Monastir ( UM ), Institut Mondor de Recherche Biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Bioprédic International, Nutrition, Métabolismes et Cancer ( NuMeCan ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), H2P2 - Histo Pathologie Hight Precision ( H2P2 ), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ), Université de Monastir - University of Monastir (UM), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Nutrition, Métabolismes et Cancer (NuMeCan), Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), H2P2 - Histo Pathologie Hight Precision (H2P2), Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Tunisian Ministry of Higher Education and Scientific Research, Jonchère, Laurent, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes 1 (UR1)

Subjects
0301 basic medicine, Physiology, medicine.medical_treatment, thymoquinone, Pharmacology, medicine.disease_cause, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, hepatectomy, Physiology (medical), medicine, oxidative stress, Thymoquinone, Liver injury, [ SDV ] Life Sciences [q-bio], Chemistry, Endoplasmic reticulum, apoptosis, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, Liver regeneration, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 030104 developmental biology, Apoptosis, 030220 oncology & carcinogenesis, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Unfolded protein response, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, endoplasmic reticulum stress, Hepatectomy, Oxidative stress, Ischemia reperfusion injury
Abstract

International audience; Ischemia reperfusion (I/R) is associated with liver injury and impaired regeneration during partial hepatectomy (PH). The aim of this study was to investigate the effect of thymoquinone (TQ), the active compound of essential oil obtained from Nigella sativa seeds, on rat liver after PH. Male Wistar rats were equally divided into four groups (n=6) receiving an oral administration of either vehicle solution (Sham and PH groups) or TQ at 30 mg/kg (TQ and TQ+PH groups) for ten consecutive days. Then, rats underwent PH (70%) with 60 min of ischemia followed by 24h of reperfusion (PH and TQ+PH groups). Alanine aminotransferase (ALT) activity and histopathological damage were determined. Also, antioxidant parameters, liver regeneration index, hepatic adenosine triphosphate (ATP) content, endoplasmic reticulum (ER) stress and apoptosis were assessed. In response to PH under I/R, liver damage was significantly alleviated by TQ treatment as evidenced by the decrease in ALT activity (P < 0.01) and histological findings (P < 0.001). In parallel, TQ preconditioning increased hepatic antioxidant capacities. Moreover, TQ improved mitochondrial function (ATP, P < 0.05), attenuated ER stress parameters and repressed the expression of apoptotic effectors. Taken together, our results suggest that TQ preconditioning could be an effective strategy to reduce liver injury after PH under I/R. The protective effects were mediated by the increase of antioxidant capacities and the decrease of ER stress and apoptosis. This article is protected by copyright. All rights reserved.

Published
2018

13. Thymoquinone prevents endoplasmic reticulum stress and mitochondria-induced apoptosis in a rat model of partial hepatic warm ischemia reperfusion

Author

Ahlem Bouhlel, Hassen Ben Abdennebi, Anne Corlu, Roselyne Viel, Catherine Ribault, Saber Mannai, Ismail Ben Mosbah, Najet Hadj Abdallah, Bioprédic International, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), H2P2 - Histo Pathologie Hight Precision (H2P2), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), UR12ES11, Tunisian Ministry of Higher Education and Scientific Research, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
0301 basic medicine, MAPK/ERK pathway, Male, MAP Kinase Signaling System, p38 mitogen-activated protein kinases, Apoptosis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Mitochondrion, Pharmacology, medicine.disease_cause, Protective Agents, p38 Mitogen-Activated Protein Kinases, Antioxidants, 03 medical and health sciences, chemistry.chemical_compound, Ischemia, Benzoquinones, Medicine, Animals, Warm Ischemia, Phosphorylation, Rats, Wistar, Thymoquinone, business.industry, Tumor Necrosis Factor-alpha, Endoplasmic reticulum, General Medicine, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Endoplasmic Reticulum Stress, Mitochondria, Rats, Oxidative Stress, 030104 developmental biology, chemistry, Liver, Reperfusion Injury, Immunology, Reperfusion, Unfolded protein response, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Oxidative stress, Ischemia reperfusion injury
Abstract

International audience; This study was undertaken to evaluate the protective effect of thymoquinone (TQ), the bioactive compound of Nigella sativa seeds, against warm ischemia-reperfusion (I/R) injury in liver. Rats were given an oral administration of a vehicle solution (sham group) or TQ at the appropriate dose (10, 20, 30 and 40mg/kg) for ten days consecutively. Following, they were subjected to 60min of partial hepatic ischemia followed by 24h of reperfusion. .Transaminase activities, histopathological changes, TNFα and antioxidant parameters were evaluated. Also, endoplasmic reticulum (ER) stress, mitochondrial damage and apoptosis were studied. In addition, ERK and P38 phosphorylation was determined by Western blot technique. We found that TQ at 30mg/kg is the effective dose to protect rat liver against I/R injury. Moreover, 30mg/kg of TQ prevented histological damages, inflammation and oxidative stress. Interestingly, it decreased the expression of ER stress parameters including GRP78, CHOP and caspase-12. In parallel, it improved mitochondrial function and attenuated the expression of apoptotic parameters. Furthermore, TQ significantly enhanced ERK and P38 phosphorylation. In conclusion, we demonstrated the potential of TQ to protect the rat liver against I/R injury through the prevention of ER stress and mitochondrial dysfunction. These effects implicate the prevention of oxidative stress.

Published
2017

14. Implication of nigral dopaminergic lesion and repeated L-DOPA exposure in non-motor symptoms of Parkinson's disease

Author

Pierre Montagne, H. Wing Young, Bertrand Rion, Simon Loiodice, Roselyne Viel, B. Méot, C. Drieu La Rochelle, and Anne-Sophie Denibaud

Subjects
Pharmacology, Parkinson's disease, business.industry, Dopaminergic, medicine.disease, Lesion, Psychiatry and Mental health, Neurology, medicine, Non motor, Pharmacology (medical), Neurology (clinical), medicine.symptom, business, Neuroscience, Biological Psychiatry
Published
2019

15. CD95-Mediated Calcium Signaling Promotes T Helper 17 Trafficking to Inflamed Organs in Lupus-Prone Mice

Author

Patrick Blanco, Patrick Legembre, Paul A. Barrow, Aubin Penna, Cécile Contin-Bordes, Marine Malleter, Robin J. Flynn, Jerome Ritz, Thomas Ducret, Roselyne Viel, Florence Poizeau, Julien Seneschal, Alain Dupuy, Nathalie Rioux, Lucie Morere, Florence Jouan, Pierre Vacher, Matthieu Le Gallo, Alain Fautrel, Amanda Poissonnier, Edouard Forcade, Doriane Sanséau, Anne-Marie Vacher, Nicolas Levoin, Oncogenesis Stress Signaling (OSS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC), CRLCC Eugène Marquis (CRLCC), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire Bioprojet, H2P2 - Histo Pathologie Hight Precision (H2P2), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Composantes innées de la réponse immunitaire et différenciation (CIRID), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), CHU Pontchaillou [Rennes], Foie, métabolismes et cancer, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], Service d'immunologie et d'immunogénétique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux], Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Validation et identification de nouvelles cibles en oncologie (VINCO), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Bordeaux Segalen - Bordeaux 2, INCa PLBIO, Ligue Contre le Cancer, INSERM Transfert, Fondation ARC, Region Bretagne, Rennes Metropole, University of Nottingham Faculty of Medicine, Biotechnology and Biological Sciences Research Council [BB/M018369/1], ANR [ANR-12-JSV2-0004-001], ANR-12-JSV2-0004,Ca-DoS,Vivre ou Mourir : Le calcium comme point de contrôle déterminant le destin d'une cellule suite à la stimulation des récepteurs de mort.(2012), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
0301 basic medicine, Mice, Inbred MRL lpr, Lymphocyte, receptor, cd95, ligand, T-Lymphocytes, Regulatory, chemistry.chemical_compound, Mice, Sphingosine, Immunology and Allergy, Lupus Erythematosus, Systemic, Interferon gamma, Cells, Cultured, Th17 cell, Systemic lupus erythematosus, Interleukin-17, apoptosis, Fas receptor, autoimmune lymphoproliferative syndrome, 3. Good health, Cell biology, Infectious Diseases, medicine.anatomical_structure, sh3 domain, Female, Interleukin 17, Signal transduction, medicine.drug, Immunology, fas gene-mutations, Biology, 03 medical and health sciences, Interferon-gamma, Immune system, sphingosine-1 phosphate, death, medicine, Animals, Humans, Protein Interaction Domains and Motifs, Sphingosine-1-phosphate, Calcium Signaling, fas Receptor, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, Phospholipase C gamma, pathway, Transendothelial and Transepithelial Migration, lupus, medicine.disease, Peptide Fragments, Disease Models, Animal, 030104 developmental biology, chemistry, inflammation, Th17 Cells, Calcium, Lysophospholipids, Transcriptome, protein
Abstract

International audience; CD95 ligand (CD95L) is expressed by immune cells and triggers apoptotic death. Metalloprotease-cleaved CD95L (cl-CD95L) is released into the bloodstream but does not trigger apoptotic signaling. Hence, the pathophysiological role of cl-CD95L remains unclear. We observed that skin-derived endothelial cells from systemic lupus erythematosus (SLE) patients expressed CD95L and that after cleavage, cl-CD95L promoted T helper 17 (Th17) lymphocyte transmigration across the endothelial barrier at the expense of T regulatory cells. T cell migration relied on a direct interaction between the CD95 domain called calcium-inducing domain (CID) and the Src homology 3 domain of phospholipase C gamma 1. Th17 cells stimulated with cl-CD95L produced sphingosine-1-phosphate (S1P), which promoted endothelial transmigration by activating the S1P receptor 3. We generated a cell-penetrating CID peptide that prevented Th17 cell transmigration and alleviated clinical symptoms in lupus mice. Therefore, neutralizing the CD95 non-apoptotic signaling pathway could be an attractive therapeutic approach for SLE treatment.

Published
2016

16. Wild type VHL clear cell renal cell carcinomas: A distinct morphological and clinical entity with PD-L1 expression

Author

Julien Dagher, Karim Bensalah, Solène-Florence Kammerer-Jacquet, Adélaïde Pladys, Angélique Brunot, Roselyne Viel, Florence Jouan, Pierre Kerbrat, Brigitte Laguerre, Nathalie Rioux-Leclercq, Gregory Verhoest, Julien Edeline, Pascale Bellaud, and Laurence Crouzet

Subjects
Cancer Research, endocrine system diseases, Tumor suppressor gene, business.industry, Cell, Wild type, urologic and male genital diseases, medicine.disease, female genital diseases and pregnancy complications, Clear cell renal cell carcinoma, medicine.anatomical_structure, Oncology, Cancer research, medicine, Pd l1 expression, cardiovascular diseases, business, neoplasms, Clear cell
Abstract

11053 Background: Clear cell renal cell carcinoma (ccRCC) is an aggressive tumor and in most of cases, is characterized by an inactivation of the tumor suppressor gene VHL (Von Hippel-Lindau). This...

Published
2015

17. Synchronous Metastatic Clear-Cell Renal Cell Carcinoma: A Distinct Morphologic, Immunohistochemical, and Molecular Phenotype

Author

Brigitte Laguerre, Romain Mathieu, Frédéric Dugay, Marc-Antoine Belaud-Rotureau, Julien Edeline, Julien Dagher, Gregory Verhoest, Guillaume Bouzillé, Sarah Medane, Jean Mosser, Benoit Peyronnet, Nathalie Rioux-Leclercq, Angélique Brunot, Solène-Florence Kammerer-Jacquet, Adélaïde Pladys, Alexandra Lespagnol, Karim Bensalah, Service de Pathologie [Rennes] = Pathology [Rennes], CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CRLCC Eugène Marquis (CRLCC), École des Hautes Études en Santé Publique [EHESP] (EHESP), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Cytogénétique et de Biologie Cellulaire, Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Service d'urologie [Rennes] = Urology [Rennes], Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Département d'oncologie médicale [Rennes], Nutrition, Métabolismes et Cancer (NuMeCan), Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), The authors would like to acknowledge the Ligue Contre le Cancer, the CORECT, Rennes Hospital, and the French Institute of Cancer (INCa) for their financial aid.The authors would also like to thank the Center of Biological Resources of Rennes Hospital (BB-0033-00056, http://www.crbsante-rennes.com/) for managing patient samples as well as Pascale Bellaud and Roselyne Viel from the Histopathology platform H2P2-BIOSIT, Faculty of Medicine of Rennes for their technical support., Service de Pathologie [CHU Rennes], Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CRLCC Eugène Marquis ( CRLCC ), École des Hautes Études en Santé Publique [EHESP] ( EHESP ), Centre d'Investigation Clinique [Rennes] ( CIC ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Service d'urologie, Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Nutrition, Métabolismes et Cancer ( NuMeCan ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), and Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1)

Subjects
Male, Vascular Endothelial Growth Factor A, 0301 basic medicine, Oncology, Clear cell renal cell carcinoma, [ SDV.AEN ] Life Sciences [q-bio]/Food and Nutrition, Cell, Cell Cycle Proteins, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, B7-H1 Antigen, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Neoplasms, Multiple Primary, chemistry.chemical_compound, 0302 clinical medicine, Neoplasm Metastasis, Aged, 80 and over, Univariate analysis, Clinical outcome, Neoplasms, Second Primary, Middle Aged, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Prognosis, Primary tumor, VEGF, Kidney Neoplasms, 3. Good health, Gene Expression Regulation, Neoplastic, Vascular endothelial growth factor, medicine.anatomical_structure, Von Hippel-Lindau Tumor Suppressor Protein, 030220 oncology & carcinogenesis, Cohort, Immunohistochemistry, Female, Adult, medicine.medical_specialty, Urology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Diagnosis, Differential, 03 medical and health sciences, Internal medicine, Biomarkers, Tumor, medicine, Humans, Carbonic Anhydrase IX, Carcinoma, Renal Cell, VHL gene, Adaptor Proteins, Signal Transducing, Aged, Retrospective Studies, business.industry, Genetic Variation, Membrane Proteins, Synchronous and metachronous metastases, medicine.disease, Survival Analysis, Sarcomatoid component, 030104 developmental biology, chemistry, business, Clear cell
Abstract

International audience; INTRODUCTION: Clear cell renal cell carcinomas (ccRCCs) are highly metastatic tumors with metastases detected at diagnosis (synchronous) or during follow-up (metachronous). To date, there have been no reports comparing primary ccRCC of patients with synchronous and metachronous metastases, who are different in terms of prognosis. Determining whether there is a phenotypic difference between these 2 groups could have important clinical implications. PATIENTS AND METHODS: In a retrospective consecutive cohort of 98 patients with ccRCC, 48 patients had metastases, including 28 synchronous and 20 metachronous presentations, with a follow-up of 10 years. For each primary tumor in these metastatic patients, pathologic criteria, expression of vascular endothelial growth factor, partitioning-defective 3, CAIX, and programmed death ligand 1 as detected by immunohistochemistry, and complete VHL status were analyzed. Univariate analysis was performed, and survival was assessed using Kaplan-Meier curves compared by log-rank test. RESULTS: Compared with primary ccRCC in patients with metachronous metastases, primary ccRCC in patients with synchronous metastases were significantly associated with a poorer Eastern Cooperative Oncology Group performance (P = .045), higher pT status (P = .038), non-inactivated VHL gene (P = .01), sarcomatoid component (P = .007), expression of partitioning-defective 3 (P = .007), and overexpressions of vascular endothelial growth factor (> 50%) (P = .017) and programmed death ligand 1 (P = .019). Patients with synchronous metastases had a worse cancer-specific survival than patients with metachronous metastases even from metastatic diagnosis (median survival, 16 months vs. 46 months, respectively; P = .01). CONCLUSION: This long-term study is the first to support the notion that synchronous m-ccRCC has a distinct phenotype. This is probably linked to the occurrence of oncogenic events that could explain the worse prognosis. These particular patients with metastases could benefit from specific therapy.

Published
2017

18. Chlordecone potentiates hepatic fibrosis in chronic liver injury induced by carbon tetrachloride in mice

Author

Moana Gelu-Simeon, François Tiaho, Valentine Genet, Catherine Lucas-Clerc, Elise Tabet, Claire Piquet-Pellorce, Michel Samson, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire de biochimie générale, Hôpital Pontchaillou-CHU Pontchaillou [Rennes], This work was supported by Inserm, Université de Rennes 1 and the ANR (Agence nationale de la recherche, Programme CESA 2011, Acronyme : Hepatochlor). For immunohistochemistry and animal house facilities, we would like to thank the dedicated platforms (i.e. H2P2 (Pascale Bellaud and Roselyne Viel), Arche (Laurence Bernard)) of SFR BIOSIT, University of Rennes 1, France., Jonchère, Laurent, Université d'Angers (UA)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
0301 basic medicine, CCl4, Male, Insecticides, Cirrhosis, Time Factors, 010501 environmental sciences, Toxicology, Liver Cirrhosis, Experimental, 01 natural sciences, chemistry.chemical_compound, Fibrosis, Carbon Tetrachloride, education.field_of_study, Extracellular Matrix Proteins, [SDV.TOX.ECO] Life Sciences [q-bio]/Toxicology/Ecotoxicology, biology, Alanine Transaminase, General Medicine, 3. Good health, Kepone, Liver, Chlordecone, Chemical and Drug Induced Liver Injury, Chronic, Disease Progression, Collagen, [SDV.TOX.ECO]Life Sciences [q-bio]/Toxicology/Ecotoxicology, Liver cancer, medicine.medical_specialty, Population, digestive system, 03 medical and health sciences, Internal medicine, medicine, Animals, Aspartate Aminotransferases, education, 0105 earth and related environmental sciences, business.industry, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, digestive system diseases, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, Alanine transaminase, chemistry, Gene Expression Regulation, biology.protein, Liver function, Hepatic fibrosis, business, Biomarkers
Abstract

International audience; Chronic liver damage due to viral or chemical agents leads to a repair process resulting in hepatic fibrosis. Fibrosis may lead to cirrhosis, which may progress to liver cancer or a loss of liver function, with an associated risk of liver failure and death. Chlordecone is a chlorinated pesticide used in the 1990s. It is not itself hepatotoxic, but its metabolism in the liver triggers hepatomegaly and potentiates hepatotoxic agents. Chlordecone is now banned, but it persists in soil and water, resulting in an ongoing public health problem in the Caribbean area. We assessed the probable impact of chlordecone on the progression of liver fibrosis in the population of contaminated areas, by developing a mouse model of chronic co-exposure to chlordecone and a hepatotoxic agent, carbon tetrachloride (CCl4). After repeated administrations of chlordecone and CCl4 by gavage over a 12-week period, we checked for liver damage in the exposed mice, by determining serum liver transaminase (AST, ALT) levels, histological examinations of the liver and measuring the expression of genes encoding extracellular matrix components. The co-exposure of mice to CCl4 and chlordecone resulted in significant increases in ALT and AST levels. Chlordecone also increased expression of the Col1A2, MMP-2, TIMP-1 and PAI-1 genes in CCl4-treated mice. Finally, we demonstrated, by quantifying areas of collagen deposition and alpha-SMA gene expression, that chlordecone potentiated the hepatic fibrosis induced by CCl4. In conclusion, our data suggest that chlordecone potentiates hepatic fibrosis in mice with CCl4-induced chronic liver injury

Published
2015

19. The IL-33/ST2 axis is associated with human visceral leishmaniasis and suppresses Th1 responses in the livers of BALB/c mice infected with Leishmania donovani

Author

Jean-Pierre Gangneux, Michel Samson, Christelle Manuel, Octavie Rostan, Andrew N. J. McKenzie, Claude Guiguen, Claire Piquet-Pellorce, Florence Robert-Gangneux, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de Parasitologie-Mycologie [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Laboratory of Molecular Biology (LMB), Medical Research Council, Ministère de l'Enseignement Supérieur et de la Recherche. Institut de Parasitologie de l'Ouest CPER Bretagne Faculté de Médecine--Université Rennes 1 Pascal Bellaud, Roselyne Viel, Alain Fautrel SFR BIOSIT histopathology platform Gersende Lacombe cytometry platform de SFR BIOSIT Charles Mary, Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], and Lecoupe-Grainville, Marie

Subjects
MESH: Interleukin-12, medicine.medical_treatment, MESH: Mice, Knockout, Mice, 0302 clinical medicine, MESH: Animals, MESH: Receptors, Cell Surface, Mice, Knockout, Mice, Inbred BALB C, 0303 health sciences, Interleukin-12, QR1-502, 3. Good health, Cytokine, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Liver, 030220 oncology & carcinogenesis, Leishmaniasis, Visceral, Female, Research Article, MESH: Interleukins, MESH: Interferon-gamma, Leishmania donovani, MESH: Mice, Inbred BALB C, Receptors, Cell Surface, Biology, Microbiology, BALB/c, Interferon-gamma, 03 medical and health sciences, Immune system, Virology, medicine, Animals, Humans, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, MESH: Mice, 030304 developmental biology, MESH: Humans, MESH: Leishmania donovani, Interleukins, Leishmaniasis, Receptors, Interleukin, Th1 Cells, Interleukin-33, biology.organism_classification, medicine.disease, Leishmania, Interleukin-1 Receptor-Like 1 Protein, Hepatic immune response, MESH: Receptors, Interleukin, Visceral leishmaniasis, MESH: Th1 Cells, MESH: Leishmaniasis, Visceral, Immunology, MESH: Female, MESH: Liver
Abstract

During visceral leishmaniasis, the control of hepatic parasite burden is mainly due to granuloma assembly in a microenvironment consisting of both Th1 and Th2 components. Using enzyme-linked immunosorbent assay (ELISA) dosages, quantitative PCR (qPCR), immunohistochemistry, and flow cytometry, we studied the role of interleukin-33 (IL-33), a recently described cytokine signaling through the ST2 receptor, during visceral leishmaniasis. We showed that a higher level of IL-33 was detected in the serum of patients with visceral leishmaniasis than in that from healthy donors and demonstrated the presence of IL-33+ cells in a liver biopsy specimen from a patient. Similarly, in BALB/c mice experimentally infected with L. donovani, a higher level of IL-33 was detected in the serum, as well as the presence of IL-33+ cells and ST2+ cells in the mouse liver. In ST2−/− BALB/c mice, better control of the hepatic parasite burden and reduced hepatomegaly were observed. This was associated with strong induction of Th1 cytokines (gamma interferon [IFN-γ] and IL-12) compared to the level in wild-type (WT) mice and better recruitment of myeloid cells associated with strongly induced chemokines (CCL2 and CXCL2) and receptors (CCR2 and CXCR2). Conversely, BALB/c mice treated twice weekly with recombinant IL-33 showed a dramatically reduced induction of Th1 cytokines and delayed inhibition of monocyte and neutrophil recruitment in the liver, which was associated with reduced KC/CXCL1 and CXCR2 expression. Taken together, our results suggest that IL-33 could be a new deleterious regulator of the hepatic immune response against Leishmania donovani, via the repression of the Th1 response and myeloid cell recruitment., IMPORTANCE Visceral leishmaniasis is a life-threatening systemic disease due to the Leishmania protozoa L. infantum and L. donovani and is ranked by the World Health Organization as the second most important protozoan parasitic disease after malaria for its grave morbidity, high mortality, and global distribution. Leishmania parasites subvert the host’s immune response to propagate to target organs, including the spleen, the bone marrow, and the liver. Control of hepatic parasite burdens depends on a delicate and poorly understood Th1/Th2 immune balance. To better understand this complex immune response, new cytokines are interesting targets for research studies. IL-33 is a newly described cytokine usually associated with Th2 response and involved in different diseases, including infectious diseases and hepatitis. Our results suggest that IL-33 could be a new factor of susceptibility and a potential prognostic marker during visceral leishmaniasis.

Published
2013

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