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1. Sigma 1 Receptor is Overexpressed in Hepatocellular Adenoma: Involvement of ERα and HNF1α

Author

Sylvie Prigent, Fabienne Foufelle, Jessica Zucman-Rossi, Marco Pontoglio, Magali Chiral, Sandra Rebouissou, Stefano Caruso, Eric Chevet, Laure Villemain, Aurélie Abou-Lovergne, Laura Pelletier, Laurent Combettes, Raphael Pineau, UMR-S1174, Institut National de la Santé et de la Recherche Médicale (INSERM), Intéractions cellulaires et physiopathologie hépathique (Orsay, Essonne) UMRS 1174 (ICPH ), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), 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), CRLCC Eugène Marquis (CRLCC), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), R16173CC, Fondation ARC pour la Recherche sur le Cancer, R17167CC and R18159CC, Ligue Nationale contre le Cancer, INCA_7981, Institut National Du Cancer, École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), and Jonchère, Laurent

Subjects
0301 basic medicine, Cancer Research, liver tumor, Liver tumor, medicine.drug_class, proliferation, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, lcsh:RC254-282, Article, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Lipid droplet, medicine, hepatocyte, steatosis, Sigma-1 receptor, Hepatocellular adenoma, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, digestive system diseases, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Oncology, Nuclear receptor, Estrogen, 030220 oncology & carcinogenesis, Hepatocyte, Knockout mouse, Cancer research
Abstract

Sigma receptor 1 (SigR1) is an endoplasmic reticulum resident integral membrane protein whose functions remain unclear. Although the liver shows the highest expression of SigR1, its role in this organ is unknown. SigR1 is overexpressed in many cancers and its expression is correlated to hormonal status in hormone-dependent cancers. To better understand the role of SigR1 in hepatocytes we focused our work on the regulation of its expression in tumoral liver. In this context, hepatocellular adenomas, benign hepatic tumors associated with estrogen intake are of particular interest. The expression of SigR1 mRNA was assessed in hepatocellular adenoma (HCA) patients using qPCR. The impact of estrogen on the expression of SigR1 was studied in vivo (mice) and in vitro (HepG2 and Huh7 cells). The effect of HNF1&alpha, on the expression of SigR1 was studied in vivo by comparing wild type mice to HNF1 knockout mice. Estrogen enhanced SigR1 expression through its nuclear receptor ER&alpha, HNF1&alpha, mutated HCA (H-HCA) significantly overexpressed SigR1 compared to all other HCA subtypes. HNF1 knockout mice showed an increase in SigR1 expression. Overexpressing SigR1 in cellular models increases proliferation rate and storage of lipid droplets, which phenocopies the H-HCA phenotype. SigR1 is involved in hepatocyte proliferation and steatosis and may play an important role in the control of the H-HCA phenotype.

Published
2020

2. A guide to assessing Endoplasmic Reticulum homeostasis and stress in mammalian systems

Author

Daria Sicari, Aeid Igbaria, Laurent Combettes, Eric Chevet, Agnès Delaunay-Moisan, Chemistry, Oncogenesis, Stress and Signaling (COSS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), CRLCC Eugène Marquis (CRLCC), Stress Oxydatif et Cancer (SOC), Département Biologie Cellulaire (BioCell), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Intéractions cellulaires et physiopathologie hépathique (Orsay, Essonne) UMRS 1174 (ICPH ), Institut National de la Santé et de la Recherche Médicale (INSERM), AcknowledgementsThis work was funded by grants from InstitutNational du Cancer (INCa PLBIO), Fondation pourla Recherche Medicale (FRM,equipe labellisee 2018),ANR (ERAAT), MSCA RISE-734749 (INSPIRED)grants to EC. DS was supported by an AIRC fellow-ship for Abroad., and Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Activating transcription factor, ER redox state, ER structure, UPR, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Endoplasmic Reticulum, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Animals, Homeostasis, Humans, Molecular Biology, Secretory pathway, Kinase, Endoplasmic reticulum, Cell Biology, Endoplasmic Reticulum Stress, Transmembrane protein, Cell biology, 030104 developmental biology, Calcium distribution, 030220 oncology & carcinogenesis, Unfolded protein response, Unfolded Protein Response, Signal transduction, ER stress, Signal Transduction
Abstract

International audience; The endoplasmic reticulum (ER) is a multifunctional organelle that constitutes the entry into the secretory pathway. The ER contributes to the maintenance of cellular calcium homeostasis, lipid synthesis and productive secretory, and transmembrane protein folding. Physiological, chemical, and pathological factors that compromise ER homeostasis lead to endoplasmic reticulum stress (ER stress). To cope with this situation, cells activate an adaptive signaling pathway termed the unfolded protein response (UPR) that aims at restoring ER homeostasis. The UPR is transduced through post‐translational, translational, post‐transcriptional, and transcriptional mechanisms initiated by three ER‐resident sensors, inositol‐requiring protein 1α, activating transcription factor 6α, and PRKR‐like endoplasmic reticulum kinase. Determining the in and out of ER homeostasis control and UPR activation still represents a challenge for the community. Hence, standardized criteria and methodologies need to be proposed for monitoring ER homeostasis and ER stress in different model systems. Here, we summarize the pathways that are activated during ER stress and provide approaches aimed at assess ER homeostasis and stress in vitro and in vivo mammalian systems that can be used by researchers to plan and interpret experiments. We recommend the use of multiple assays to verify ER stress because no individual assay is guaranteed to be the most appropriate one.

Published
2020

3. TGR5-dependent hepatoprotection through the regulation of biliary epithelium barrier function

Author

Jose Ursic-Bedoya, Isabelle Doignon, Hayat Simerabet, Dominique Rainteau, Doris Cassio, Nicolas Kahale, Anne Davit-Spraul, Thierry Tordjmann, Grégory Merlen, Lydie Humbert, Catherine Guettier, Julien Gautherot, Valeska Bidault-Jourdainne, Christoph Ullmer, Isabelle Garcin, Noémie Péan, Klaus Ebnet, Zahra Tanfin, Intéractions cellulaires et physiopathologie hépathique (Orsay, Essonne) UMRS 1174 (ICPH ), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11), Service de Biochimie [AP-HP Hôpital Bicêtre], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Service d’Anatomopathologie [Le Kremlin-Bicêtre], ER_7, Université Pierre et Marie Curie - Paris 6 (UPMC), Microorganismes, Molécules Bioactives et Physiopathologie Intestinale (LBM-E4), Institut National de la Santé et de la Recherche Médicale (INSERM)-Laboratoire des biomolécules (LBM UMR 7203), Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Chimie Moléculaire de Paris Centre (FR 2769), Institut de Chimie du CNRS (INC)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Microorganismes et physiopathologie intestinale (ERL INSERM U1157 - CNRS UMR 7203), Laboratoire des biomolécules (LBM UMR 7203), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC), Zentrum für Molekularbiologie der Entzündung - Center for Molecular Biology of Inflammation [Münster, Germany] (ZMBE), Westfälische Wilhelms-Universität Münster (WWU), F. Hoffmann-La Roche [Basel], Chimie Moléculaire de Paris Centre (FR 2769), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Chimie Moléculaire de Paris Centre (FR 2769), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Westfälische Wilhelms-Universität Münster = University of Münster (WWU), and Salvy-Córdoba, Nathalie

Subjects
Biliary epithelium, MESH: Signal Transduction, Stimulation, MESH: Receptors, G-Protein-Coupled, MESH: Mice, Knockout, Epithelium, Receptors, G-Protein-Coupled, MESH: Isonipecotic Acids, 0302 clinical medicine, MESH: Biliary Tract, Oximes, Electric Impedance, Bile, MESH: Animals, Phosphorylation, Biliary Tract, Cells, Cultured, Barrier function, MESH: Receptors, Cell Surface, Mice, Knockout, Liver injury, 0303 health sciences, Bile acid, Tight junction, Chemistry, Gastroenterology, MESH: Oximes, G protein-coupled bile acid receptor, Paracellular transport, MESH: Permeability, Cholestaticliver diseases, MESH: Cell Adhesion Molecules, 030211 gastroenterology & hepatology, Signal Transduction, MESH: Cells, Cultured, medicine.drug_class, MESH: Tight Junction Proteins, Receptors, Cell Surface, Cholestasis, Intrahepatic, MESH: Bile Acids and Salts, Permeability, Bile Acids and Salts, 03 medical and health sciences, Isonipecotic Acids, In vivo, MESH: Mice, Inbred C57BL, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Electric Impedance, MESH: Bile, 030304 developmental biology, Tight Junction Proteins, MESH: Phosphorylation, MESH: Cholestasis, Intrahepatic, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, Molecular biology, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Mice, Inbred C57BL, MESH: Epithelium, Cell Adhesion Molecules
Abstract

ObjectiveWe explored the hypothesis that TGR5, the bile acid (BA) G-protein-coupled receptor highly expressed in biliary epithelial cells, protects the liver against BA overload through the regulation of biliary epithelium permeability.DesignExperiments were performed under basal and TGR5 agonist treatment. In vitro transepithelial electric resistance (TER) and FITC-dextran diffusion were measured in different cell lines. In vivo FITC-dextran was injected in the gallbladder (GB) lumen and traced in plasma. Tight junction proteins and TGR5-induced signalling were investigated in vitro and in vivo (wild-type [WT] and TGR5-KO livers and GB). WT and TGR5-KO mice were submitted to bile duct ligation or alpha-naphtylisothiocyanate intoxication under vehicle or TGR5 agonist treatment, and liver injury was studied.ResultsIn vitro TGR5 stimulation increased TER and reduced paracellular permeability for dextran. In vivo dextran diffusion after GB injection was increased in TGR5-knock-out (KO) as compared with WT mice and decreased on TGR5 stimulation. In TGR5-KO bile ducts and GB, junctional adhesion molecule A (JAM-A) was hypophosphorylated and selectively downregulated among TJP analysed. TGR5 stimulation induced JAM-A phosphorylation and stabilisation both in vitro and in vivo, associated with protein kinase C-ζ activation. TGR5 agonist-induced TER increase as well as JAM-A protein stabilisation was dependent on JAM-A Ser285 phosphorylation. TGR5 agonist-treated mice were protected from cholestasis-induced liver injury, and this protection was significantly impaired in JAM-A-KO mice.ConclusionThe BA receptor TGR5 regulates biliary epithelial barrier function in vitro and in vivo through an impact on JAM-A expression and phosphorylation, thereby protecting liver parenchyma against bile leakage.

Published
2019

4. P2X7 receptor promotes intestinal inflammation in chemically induced colitis and triggers death of mucosal regulatory T cells

Author

Vanessa Ribeiro Figliuolo, Heitor Siffert Pereira de Souza, Pierre Bobé, Claudio Bernardazzi, Hanaa Safya, Cláudia Mara Lara Melo Coutinho, Hayandra F. Nanini, Jean Kanellopoulos, Luiz Eduardo Baggio Savio, Robson Coutinho-Silva, Alessandra Alves Abalo, Intéractions cellulaires et physiopathologie hépathique (Orsay, Essonne) UMRS 1174 (ICPH ), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 (UP11), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut André Lwoff - Biologie intégrée de la cellule, virus et cancer (IALBICVC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11), and Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, colitis, Regulatory T cell, T-Lymphocytes, [SDV]Life Sciences [q-bio], Inflammation, Biology, Inflammatory bowel disease, regulatory T cells, Mice, 03 medical and health sciences, Immune system, medicine, Animals, Mesenteric lymph nodes, IL-2 receptor, Intestinal Mucosa, Colitis, Immunity, Mucosal, Molecular Biology, Mice, Knockout, Oxazolone, FOXP3, Inflammatory Bowel Diseases, medicine.disease, 3. Good health, ATP, 030104 developmental biology, medicine.anatomical_structure, Trinitrobenzenesulfonic Acid, P2X7 receptor, Immunology, Molecular Medicine, Female, Receptors, Purinergic P2X7, medicine.symptom
Abstract

P2X7 receptor activation contributes to inflammation development in different pathologies. We previously reported that the P2X7 receptor is over-expressed in the gut mucosa of patients with inflammatory bowel disease, and that P2X7 inhibition protects against chemically induced colitis. Here, we investigated in detail the role of the P2X7 receptor in inflammatory bowel disease development, by treating P2X7 knockout (KO) and WT mice with two different (and established) colitis inductors. P2X7 KO mice were protected against gut inflammation induced by 2,4,6-trinitrobenzenesulfonic acid or oxazolone, with no weight loss or gut histological alterations after treatment. P2X7 receptor knockout induced regulatory T cell accumulation in the colon, as evaluated by qRT-PCR for FoxP3 expression and immunostaining for CD90/CD45RB(low). Flow cytometry analysis of mesenteric lymph node cells showed that P2X7 activation (by ATP) triggered regulatory T cell death. In addition, such cells from P2X7 KO mice expressed more CD103, suggesting increased migration of regulatory T cells to the colon (relative to the WT). Our results show that the P2X7 has a key role during inflammation development in inflammatory bowel disease, by triggering the death and retention in the mesenteric lymph nodes of regulatory T cells that would otherwise promote immune system tolerance in the gut.

Published
2017

5. Sigma 1 Receptor : Role in Hepatocyte Proliferation and Steatosis

Author

Villemain Le Hagre, Laure, Intéractions cellulaires et physiopathologie hépathique (Orsay, Essonne) UMRS 1174 (ICPH ), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Saclay (COmUE), Laurent Combettes, and STAR, ABES

Subjects
Steatosis, Stéatose, Proliferation, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Prolifération, Hepatocellular adenoma, Adénome hépatocellulaire
Abstract

Sigma 1 receptor (SigR1) is a transmembrane protein of the RE, enriched in the MAMs, which would act like a chaperone. Although ubiquitous, SigR1 is especially expressed in the central nervous system (CNS) and the liver. In the CNS, SigR1 has been linked to neurodegenerative diseases and also pain and depression. SigR1 is also involved in cancer. SigR1 is overexpressed in many cancer tumors and especially in hormone dependent tumors where its expression is correlated to the hormonal status of the tumor. Although SigR1 is highly expressed in the liver, its role in this organ is unknown. Aiming at finding the role of this protein in the liver we analyze its expression in several liver tumors. SigR1 is significantly overexpressed in hepatocellular adenomas mutated for HNF1α gene, H-HCA. H-HCA are benign liver tumors with marked steatosis. They are mostly found in women taking oral contraceptives (estrogens). Why is SigR1 overexpressed in H-HCA ans what are the consequences of this overexpression? Using hepatocyte cellular models (HepG2 and Huh7) and mice that are KO for HNF1α gene, we found the following results. Estrogens induce the expression of SigR1 through its nuclear receptor ERα. HNF1α inhibition also induces its expression. This overexpression leads to an increase of the cell proliferation rate and steatosis. These effects resume H-HCA patients’ phenotype., Le récepteur Sigma 1 (SigR1) est une protéine transmembranaire du RE, enrichie dans les MAMs, qui agirait comme une chaperonne. Ubiquitaire, SigR1 est très exprimé dans le système nerveux central (SNC) et le foie. Dans le SNC, SigR1 est impliqué dans un grand nombre de maladies neurodégénératives mais aussi dans le mécanisme de la douleur et dans la dépression. SigR1 est aussi impliqué dans les cancers. Il est surexprimé dans de nombreuses tumeurs cancéreuses et particulièrement dans les tumeurs hormonodépendantes dans lesquelles son expression est corrélée au statut hormonal de la tumeur. Malgré sa très forte expression dans le foie, son rôle y est inconnu. Dans l’objectif de déterminer le rôle de SigR1 dans le foie nous étudions son expression dans les différents types de tumeurs hépatiques. SigR1 est significativement surexprimé dans les adénomes hépatocellulaires (HCA) et particulièrement le sous-type muté pour le gène HNF1α, les H-HCA. Les H-HCA sont des tumeurs hépatiques bénignes stéatosées majoritairement observées chez des femmes jeunes prenant des contraceptifs oraux (œstrogènes). Quelles sont les causes et les conséquences de cette surexpression dans les hépatocytes ? En utilisant des modèles cellulaires hépatocytaires (HepG2 et Huh7) et des souris KO pour le gène HNF1α nous mettons en évidence les résultats suivants. Les œstrogènes induisent l’expression de SigR1 via son récepteur nucléaire ERα. De même, l’inhibition d’HNF1α induit une surexpression de SigR1. Cette surexpression entraine une prolifération et une stéatose des hépatocytes, correspondant au phénotype des patientes atteintes de H-HCAs.

Published
2019

6. Targeted Pharmacotherapy for Progressive Familial Intrahepatic Cholestasis type 2 (PFIC2)

Author

Amzal, Rachida, STAR, ABES, Intéractions cellulaires et physiopathologie hépathique (Orsay, Essonne) UMRS 1174 (ICPH ), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Saclay (COmUE), and Emmanuel Gonzales

Subjects
Mutations faux sens, 4-Phénylbutyrate, Non-Sense mutations, Missense mutations, Drogues chaperones, Chaperone drugs, Progressive familial intrahepatic cholestasis type 2, Mutations non sens, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Transporteur des sels biliaires (BSEP), [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology
Abstract

ABCB11/BSEP is the main bile acids transporter located at the canalicular pole of hepatocytes. Mutations of ABCB11 are responsible for progressive familial intrahepatic cholestasis type 2.During my phD, I evaluated the ability of aminoglycosides and PTC124 to induce readthrough of premature termination codons, targeting and function of nonsense and missense mutants of Bsep and also the effect of combined therapy (readthrough + chaperone).In our expermental models, gentamicin increased readthrough of p.R1090X mutation NIH3T3, HEK293 and Can 10 lines. The resulting full-length protein was detected at the plasma membrane of HEK293 and at the canalicular membrane of Can 10 cells; and was partially functional since it was responsible for increasing the transport activity of 3H-taurocholate (3H-TC) in MDCK clones. These effects were potentiated by the addition of chaperone drugs such as 4-phenylbutyrate (4-PB).I have also demonstrated the ability of new 4-PB derived compounds (MHMPB, OTNC and HMPB) to correct mistrafficking and to increase 3H-TC transport of BsepR1128C missense mutant at lower concentrations than 4-PB. Finally, I showed that other chaperone drugs (GPB, PA, SAHA, and C18) were able to correct mistrafiking of BsepR1128C and to increase its 3H-TC transport activity in MDCK clones., ABCB11/BSEP est le transporteur des acides biliaires, localisé au niveau du pôle canaliculaire des hépatocytes. Les mutations de ce gène sont responsables de la cholestase familiale intrahépatique progressive de type 2.Au cours de ma thèse, j’ai évalué la capacité des aminoglycosides et du PTC124 à induire la translecture de codons stop prématurés, l’adressage et la fonction de mutants non-sens et faux sens de Bsep ainsi que l’effet d’une bithérapie (translecture+chaperone).Dans nos modèles cellulaires, la gentamicine était capable d’induire la translecture du codon-stop prématuré du mutant non-sens BsepR1090X dans les lignées NIH3T3, HEK293 et Can 10. La protéine entière générée était partiellement détectée aux membranes plasmiques des cellules HEK293 et canaliculaires des cellules Can 10 et était partiellement fonctionnelle puisqu’elle était responsable d’une augmentation de l’activité de transport de 3H-taurocholate (3H-TC) dans les clones MDCK. Ces effets étaient potentialisés par l’addition de drogues chaperones telles que le 4-phenylbutyrate (4-PB).J’ai également mis en évidence la capacité de nouveaux composés dérivés du 4-PB (MHMPB, OTNC et HMPB) à corriger l’adressage et à augmenter le transport de 3H-TC du mutant faux sens BsepR1128C à des concentrations plus faibles que le 4-PB. Enfin, j’ai pu montrer que d'autres drogues chaperones (GPB, PA, SAHA et C18), pouvaient corriger l’adressage canaliculaire de BsepR1128C et augmenter son activité de transport de 3H-TC dans les clones MDCK.

Published
2019

7. Experimental and modeling study of the formation of cell aggregates with differential substrate adhesion

Author

Basile Grammaticos, Marjorie Juchaux, Christophe Deroulers, Olivier Seksek, Mathilde Badoual, Emilie Gontran, Léo Adenis, Imagerie et Modélisation en Neurobiologie et Cancérologie (IMNC (UMR_8165)), Université Paris-Sud - Paris 11 (UP11)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Intéractions cellulaires et physiopathologie hépathique (Orsay, Essonne) UMRS 1174 (ICPH ), Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported through a grant of CD from Région Ile-de-France (‘DIM Problématiques transversales aux systèmes complexes ISC-2014-PME-003') and a grant of MB and OS from the GEFLUC association (association des Entreprises Françaises dans la Lutte contre le Cancer)., and Bodescot, Myriam

Subjects
0301 basic medicine, Cell Culture Techniques, [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Systems Science, Polyethylene Glycols, Mathematical and Statistical Techniques, 0302 clinical medicine, Agent-Based Modeling, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Medicine and Health Sciences, Polylysine, Materials, Neurological Tumors, Cell Aggregation, Cultured Tumor Cells, Mass Diffusivity, 0303 health sciences, Multidisciplinary, Chemistry, Simulation and Modeling, Physics, Hydrogels, Glioma, Adhesion, Cell aggregation, Curve Fitting, Oncology, Neurology, 030220 oncology & carcinogenesis, Physical Sciences, Self-healing hydrogels, Medicine, Biological Cultures, Research Article, Computer and Information Sciences, Amorphous Solids, Science, Materials Science, Context (language use), Research and Analysis Methods, Models, Biological, Cell Line, 03 medical and health sciences, Adhesives, Cell Adhesion, Humans, Cell Proliferation, 030304 developmental biology, Chemical Physics, Aggregate (data warehouse), Spheroid, Cancers and Neoplasms, Substrate (chemistry), Cell Cultures, Glioma Cells, Kinetics, 030104 developmental biology, Mixtures, Biophysics, Adhesive, Gels, Mathematical Functions, Mathematics, 030217 neurology & neurosurgery
Abstract

The study of cell aggregation in vitro has a tremendous importance these days. In cancer biology, aggregates and spheroids serve as model systems and are considered as pseudo-tumors that are more realistic than 2D cell cultures. Recently, in the context of brain tumors (gliomas), we developed a new PEG-based hydrogel, with adhesive properties that can be controlled by the addition of poly(L-lysine) (PLL), and a stiffness close to the brain’s. This substrate allows the motion of individual cells and the formation of cell aggregates, and we showed that on a non-adhesive substrate (PEG without PLL is inert for cells), the aggregates are bigger and less numerous than on an adhesive substrate (with PLL).In this article, we present new experimental results on the follow-up of the formation of aggregates on our hydrogels, from the early stages (individual cells) to the late stages (aggregate compaction), in order to compare or two cell lines (F98 and U87) the aggregation process on the adhesive and non-adhesive substrates.We first show that a spaceless model of perikinetic aggregation can reproduce the experimental evolution of the number of aggregates, but not of the mean area of the aggregates. We thus develop a minimal off-lattice agent-based model, with a few simple rules reproducing the main processes that are at stack during aggregation. Our spatial model can reproduce very well the experimental temporal evolution of both the number of aggregates and their mean area, on adhesive and non-adhesive soft gels and for the two different cell lines. From the fit of the experimental data, we were able to infer the quantitative values of the speed of motion of each cell line, its rate of proliferation in aggregates and its ability to organize in 3D. We also found qualitative differences between the two cell lines regarding the ability of aggregates to compact. These parameters could be inferred for any cell line, and correlated with clinical properties such as aggressiveness and invasiveness.

Published
2020

8. Longterm Risk of Solid Organ De Novo Malignancies After Liver Transplantation: A French National Study on 11,226 Patients

Author

Guy Launoy, Pascal Lebray, Olivier Chazouillères, Claire Francoz, Thierry Lobbedez, Sylvie Radenne, Nassim Kamar, Maryline Debette-Gratien, Sébastien Dharancy, Marie-Lorraine Woehl-Jaegle, Dominique Debray, Olivier Sérée, Jean Gugenheim, Marianne Latournerie, Vincent Leroy, Martine Neau-Cransac, Pauline Houssel-Debry, Jean Hardwigsen, Mario Altieri, Faouzi Saliba, Geraldine Hery, Olivier Boillot, Alessandra Mazzola, Rémy De Mil, Filomena Conti, Claire Vanlemmens, Georges-Philippe Pageaux, Elodie Guillaume, Philip Robinson, Emmanuel Jacquemin, Christophe Duvoux, François Durand, Ephrem Salamé, Philippe Segol, Didier Samuel, Jérôme Dumortier, Armand Abergel, Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Côte de Nacre [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Hospices Civils de Lyon (HCL), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut Pascal (IP), SIGMA Clermont (SIGMA Clermont)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Hôpital Edouard Herriot [CHU - HCL], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Pathologies biliaires, fibrose et cancer du foie [CRSA], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service d'Hépato-Gastro-Entérologie et Nutrition [CHU Limoges], CHU Limoges, Pharmacologie des Immunosuppresseurs et de la Transplantation (PIST), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de pédiatrie multidisciplinaire [Hôpital de la Timone Enfants - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Henri Mondor [Créteil], Centre Hospitalier Universitaire de Nice (CHU Nice), Hôpital Universitaire Pontchaillou, Intéractions cellulaires et physiopathologie hépathique (Orsay, Essonne) UMRS 1174 (ICPH ), Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Néphrologie - Hypertension Artérielle Dialyse - Transplantation, Equipe EPICAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Service d'hépato-gastroentérologie et cancérologie digestive (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre hépato-biliaire (CHB), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie et traitement des maladies du foie, Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hépatologie, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Pôle des Pathologies Digestives Hépatiques et Transplantation [Hôpital Hautepierre-Strasbourg], Hôpital de Hautepierre [Strasbourg], Pathologies biliaires, fibrose et cancer du foie [CHU Saint-Antoine], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Université de Limoges (UNILIM)-CHU Limoges, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), CHU Henri Mondor, CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), CHU Saint-Eloi, Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Paul Brousse-Université Paris-Sud - Paris 11 (UP11), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), and UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER

Subjects
Adult, Male, Alcoholic liver disease, medicine.medical_specialty, Time Factors, medicine.medical_treatment, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, 030230 surgery, Liver transplantation, Gastroenterology, Risk Assessment, Liver transplantation (LT), End Stage Liver Disease, 03 medical and health sciences, 0302 clinical medicine, Postoperative Complications, Risk Factors, Internal medicine, Neoplasms, medicine, Humans, education, Liver Diseases, Alcoholic, Transplantation, education.field_of_study, Hepatology, business.industry, Incidence (epidemiology), Incidence, Absolute risk reduction, Middle Aged, medicine.disease, Confidence interval, 3. Good health, Liver Transplantation, Standardized mortality ratio, Treatment Outcome, 030211 gastroenterology & hepatology, Surgery, Female, France, Risk assessment, business, Follow-Up Studies
Abstract

IF 3.756; International audience; De novo malignancies are one of the major late complications and causes of death after liver transplantation (LT). Using extensive data from the French national Agence de la Biomédecine database, the present study aimed to quantify the risk of solid organ de novo malignancies (excluding nonmelanoma skin cancers) after LT. The incidence of de novo malignancies among all LT patients between 1993 and 2012 was compared with that of the French population, standardized on age, sex, and calendar period (standardized incidence ratio; SIR). Among the 11,226 LT patients included in the study, 1200 de novo malignancies were diagnosed (10.7%). The risk of death was approximately 2 times higher in patients with de novo malignancy (48.8% versus 24.3%). The SIR for all de novo solid organ malignancies was 2.20 (95% confidence interval [CI], 2.08‐2.33). The risk was higher in men (SIR = 2.23; 95% CI, 2.09‐2.38) and in patients transplanted for alcoholic liver disease (ALD; SIR = 2.89; 95% CI, 2.68‐3.11). The cancers with the highest excess risk were laryngeal (SIR = 7.57; 95% CI, 5.97‐9.48), esophageal (SIR = 4.76; 95% CI, 3.56‐6.24), lung (SIR = 2.56; 95% CI, 2.21‐2.95), and lip‐mouth‐pharynx (SIR = 2.20; 95% CI, 1.72‐2.77). In conclusion, LT recipients have an increased risk of de novo solid organ malignancies, and this is strongly related to ALD as a primary indication for LT.

Published
2018

9. Characterization of neutralizing antibodies reacting with the 213-224 amino-acid segment of human galectin-9

Author

Lhuillier, Claire, Barjon, Clément, Baloche, Valentin, Niki, Toshiro, Gelin, Aurore, Mustapha, Rami, Claër, Laetitia, Hoos, Sylviane, Chiba, Yoichi, Ueno, Masaki, Hirashima, Mitsuomi, Wei, Ming, Moralès, Olivier, Raynal, Bertrand, Delhem, Nadira, Dellis, Olivier, Busson, Pierre, Signalisation, noyaux et innovations en cancérologie (UMR8126), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Kagawa University [Japan], Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), H-Immune Therapeutics [Paris], Biophysique Moléculaire (Plate-forme), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Cellvax, École nationale vétérinaire d'Alfort (ENVA), Intéractions cellulaires et physiopathologie hépathique (Orsay, Essonne) UMRS 1174 (ICPH ), Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by Idex Saclay - Satt Saclay, Prematuration Grant 2015, https://www.satt-paris-saclay.fr, BMS Foundation for Immuno-Oncology- Grant 2016-2017, http://fondation-bms.fr/. Several authors were employed by commercial companies: Cellvax (CL, CB, MW), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and École nationale vétérinaire - Alfort (ENVA)

Subjects
MESH: T-Lymphocytes/metabolism, MESH: Apoptosis/drug effects, MESH: Biological Transport, [SDV]Life Sciences [q-bio], MESH: T-Lymphocytes/drug effects, MESH: Galectins/adverse effects, Lactose, MESH: Galectins/immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, MESH: Antibodies, Neutralizing/pharmacology, Antibodies, MESH: T-Lymphocytes/cytology, MESH: Jurkat Cells, MESH: Animals, Flow cytometry, Enzyme-linked immunoassays, MESH: Mice, MESH: Antibodies, Monoclonal/pharmacology, Antibody isotypes, MESH: Humans, MESH: Calcium/metabolism, MESH: Epitopes/immunology, Cell staining, MESH: Galectins/chemistry, Apoptosis T cells, MESH: Immunization, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Phosphatidylserines/metabolism
Abstract

International audience; Extra-cellular galectin-9 (gal-9) is an immuno-modulatory protein with predominant immuno-suppressive effects. Inappropriate production of gal-9 has been reported in several human malignancies and viral diseases like nasopharyngeal, pancreatic and renal carcinomas, metastatic melanomas and chronic active viral hepatitis. Therefore therapeutic antibodies neutralizing extra-cellular gal-9 are expected to contribute to immune restoration in these pathological conditions. Two novel monoclonal antibodies targeting gal-9-Gal-Nab 1 and 2-have been produced and characterized in this study. We report a protective effect of Gal-Nab1 and Gal-Nab2 on the apoptotic cell death induced by gal-9 in primary T cells. In addition, they inhibit late phenotypic changes observed in peripheral T cells that survive gal-9-induced apoptosis. Gal-Nab1 and Gal-Nab2 bind nearly identical, overlapping linear epi-topes contained in the 213-224 amino-acid segments of gal-9. Nevertheless, they have some distinct functional characteristics suggesting that their three-dimensional epitopes are distinct. These differences are best demonstrated when gal-9 is applied on Jurkat cells where Gal-Nab1 is less efficient than Gal-Nab2 in the prevention of apoptotic cell death. In addition, Gal-Nab1 stimulates non-lethal phosphatidylserine translocation at the plasma membrane and calcium mobilization triggered by gal-9 in these cells. Both Gal-Nab1 and 2 cross-react with murine gal-9. They bind its natural as well as its recombinant form. This cross-species recognition will be an advantage for their assessment in pre-clinical tumor models.

Published
2018

10. Towards a RAS mutation status in a single day for patients with advanced colorectal cancers. Authors' Reply

Author

Astrid Lièvre, Pierre Laurent-Puig, Pascal Artru, Michel Ducreux, Jean-Louis Merlin, Jean-Christophe Sabourin, CHU Pontchaillou [Rennes], Chemistry, Oncogenesis, Stress and Signaling (COSS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre de Recherche en Automatique de Nancy (CRAN), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), UNICANCER, CHU Rouen, Normandie Université (NU), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Intéractions cellulaires et physiopathologie hépathique (Orsay, Essonne) UMRS 1174 (ICPH ), Institut National de la Santé et de la Recherche Médicale (INSERM), Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), Sanofi, Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), and Jonchère, Laurent

Subjects
Oncology, medicine.medical_specialty, Colorectal cancer, colorectal cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Test request, RAS mutation, Test report, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Humans, Medicine, turnaround time, Massive parallel sequencing, Hepatology, business.industry, Gastroenterology, [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, 3. Good health, Genes, ras, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, quality, Mutation, RAS Mutation, Colorectal Neoplasms, business
Abstract

International audience; We thank Dr. Barel et al. for their letter concerning our article [1]. In this letter, the authors reported their experience of 1264 RAS tests performed between 2015 and 2017 in a French area of Brittany using a massively parallel sequencing method. Even if the mean duration between receipt of tumour samples by the molecular genetics platform and the transmission of the RAS test report was shorter than that we previously reported (11.03 days versus 19.5 in our study), it exceeds anyway the recommended duration between test request and results feedback [2–4].

Published
2018

11. Rôle des récepteurs purinergiques P2X7 et d'apoptose Fas dans l'homéostasie des lymphocytes T et le développement des maladies auto-immunes

Author

Mellouk, Amine, Intéractions cellulaires et physiopathologie hépathique (Orsay, Essonne) UMRS 1174 (ICPH ), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Saclay (COmUE), Pierre Bobé, and STAR, ABES

Subjects
Lymphocytes T, [SDV.IMM] Life Sciences [q-bio]/Immunology, Fas receptor, Homéostasie, T lymphocytes, Récepteur Fas, Autoimmunity, [SDV.CAN]Life Sciences [q-bio]/Cancer, Récepteur P2X7, [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], [SDV.CAN] Life Sciences [q-bio]/Cancer, immune system diseases, P2X7 receptor, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Homeostasis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Autoimmunité, skin and connective tissue diseases
Abstract

My project aims to determine the role of the purinergic receptor P2X7 (P2X7R) in the pathophysiological processes involved in the development of autoimmune lupus-like syndrome. MRL/lpr mice, deficient for the cell death receptor Fas (lpr mutation), spontaneously develop this pathology following the accumulation of pathogenic B220+CD4−CD8− (DN) T lymphocytes in secondary lymphoid organs. We have observed that these lymphocytes are also deficient in P2X7R cell surface expression. This led us to hypothesize that P2X7R could play a key role in T cell homeostasis and lupus development. To test our hypothesis, we produced B6 mice deficient for both Fas (lpr) and P2X7R (P2X7KO). These mice, but not single mutant B6 mice (lpr or P2X7KO), develop a massive accumulation of DN B220+ T lymphocytes and high levels of autoantibodies and proinflammatory cytokines, confirming for the first time the involvement of P2X7R in T-cell homeostasis. I have found that the pathogenic DN T lymphocytes are predominantly derived from the CD8+ T lymphocyte subpopulation. Chronic inflammation in B6/lpr P2X7KO mice induces the activation of the whole CD4+ and CD8+ naïve T lymphocyte subpopulations leading to the accumulation of Effector/Memory and exhausted T lymphocytes. Accumulated T-cells lose the ability to be reactivated. To confirm these results, I compared the adaptive immune response against adenovirus between mice deficient for Fas (lpr mutation), P2X7R-deficient mice or both receptors. The cellular and the humoral responses were lower in the B6/lpr-P2X7KO mouse strain compared to B6, B6-P2X7KO and B6/lpr mouse strains. The antiviral immune response in the B6/lpr mice was lower than in B6 and B6-P2X7KO mice. These results reinforce our hypothesis about the synergistic role of both receptors in the maintaining of T cell homeostasis. Ours results suggest that Fas and P2X7R play their synergistic role in T-cell homeostasis. In collaboration with a team from the University of Taiwan, we sequenced the mRNAs expressed in the spleen and lymph nodes of MRL/lpr mice before and after the onset of the diseases as well as in the B6, B6/lpr, B6 P2X7KO and B6/lpr P2X7KO mouse strains in order to better understand the mechanism triggering the disease and to identify the role of each receptor on the expression of the susceptibility loci., Mon étude a porté sur le rôle du récepteur purinergique P2X7 (P2X7R) dans les processus physiopathologiques impliqués dans le développement des maladies auto-immunes de type lupique. Les souris MRL/lpr, déficientes en récepteurs d’apoptose Fas (mutation lpr), développent spontanément ces pathologies suite à l’accumulation lymphocytes T pathogéniques CD4−CD8− (DN) B220+ dans les organes lymphoïdes secondaires. Nous avons observé que ces lymphocytes ont également un déficit d’expression en P2X7R à leur surface. Cela nous a amené à postuler que P2X7R pourrait jouer un rôle clé dans l’homéostasie des lymphocytes T et le développement du lupus. Afin de vérifier notre hypothèse, nous avons produit des souris C57BL/6J (B6) déficientes simultanément pour Fas (lpr) et P2X7R (P2X7KO). Ces souris présentent une accumulation massive de lymphocytes T DN B220+ et des titres très élevés en auto-anticorps et en cytokines proinflammatoires ce qui n’est pas le cas pour les souris B6 simples mutantes lpr ou P2X7KO confirmant pour la première fois l’implication de P2X7R dans l’homéostasie des lymphocytes T, en synergie avec le récepteur Fas. Les lymphocytes T DN pathogéniques responsables de la lymphoaccumulation sont issues majoritairement de la sous populations des lymphocytes T CD8+. L’inflammation chronique présente chez les souris B6/lpr P2X7KO induit l’activation de l’ensemble des populations lymphocytaires T CD4+ et CD8+ naïves conduisant à l’accumulation de lymphocytes T Effecteurs/Mémoires : EM et CM et atteignent parfois le stade exhausted PD1+TIM3+. Ces cellules accumulées CD4+, CD8+ et DN B220+ ont une capacité de réactivation réduite. Ce biais fonctionnel et phénotypique a été confirmé en comparant la réponse immunitaire adaptative anti-adénovirus entre des souris déficientes en Fas et/ou P2X7R. Les réponses cellulaires et humorales sont moins importantes dans les souris B6/lpr P2X7KO que B6, B6-P2X7KO. Ces réponses antivirales sont intermédiaires dans les souris B6/lpr. L’ensemble de ces résultats renforcent notre hypothèse sur le rôle synergique des récepteurs Fas et P2X7R dans l’homéostasie des lymphocytes T. Le taux d’apoptose induit par l’activation des récepteurs Fas ou P2X7R séparément est moins important dans les lymphocytes T CD8+ par rapport au lymphocytes T CD4+. La synergie Fas-P2X7R serait donc nécessaire pour l’homéostasie des lymphocytes T CD8+. Afin de préciser les mécanismes à l’origine de la maladie et d’identifier l’influence de chaque récepteur sur l’expression des loci de susceptibilité, nous avons séquencé les ARNm exprimés dans la rate et les ganglions lymphatiques des souris MRL/lpr avant et après le développement de l’auto-immunité ainsi que chez les souris B6, B6/lpr, B6 P2X7KO et B6/lpr P2X7KO.

Published
2018

12. Role of Purinergic P2X7 and Apoptosis Fas Receptors in T Lymphocyte Homeostasis and Autoimmune Desease Developpement

Author

Mellouk, Amine, Intéractions cellulaires et physiopathologie hépathique (Orsay, Essonne) UMRS 1174 (ICPH ), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Saclay (COmUE), and Pierre Bobé

Subjects
Lymphocytes T, Fas receptor, Homéostasie, T lymphocytes, Récepteur Fas, Autoimmunity, [SDV.CAN]Life Sciences [q-bio]/Cancer, Récepteur P2X7, immune system diseases, P2X7 receptor, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Homeostasis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Autoimmunité, skin and connective tissue diseases
Abstract

My project aims to determine the role of the purinergic receptor P2X7 (P2X7R) in the pathophysiological processes involved in the development of autoimmune lupus-like syndrome. MRL/lpr mice, deficient for the cell death receptor Fas (lpr mutation), spontaneously develop this pathology following the accumulation of pathogenic B220+CD4−CD8− (DN) T lymphocytes in secondary lymphoid organs. We have observed that these lymphocytes are also deficient in P2X7R cell surface expression. This led us to hypothesize that P2X7R could play a key role in T cell homeostasis and lupus development. To test our hypothesis, we produced B6 mice deficient for both Fas (lpr) and P2X7R (P2X7KO). These mice, but not single mutant B6 mice (lpr or P2X7KO), develop a massive accumulation of DN B220+ T lymphocytes and high levels of autoantibodies and proinflammatory cytokines, confirming for the first time the involvement of P2X7R in T-cell homeostasis. I have found that the pathogenic DN T lymphocytes are predominantly derived from the CD8+ T lymphocyte subpopulation. Chronic inflammation in B6/lpr P2X7KO mice induces the activation of the whole CD4+ and CD8+ naïve T lymphocyte subpopulations leading to the accumulation of Effector/Memory and exhausted T lymphocytes. Accumulated T-cells lose the ability to be reactivated. To confirm these results, I compared the adaptive immune response against adenovirus between mice deficient for Fas (lpr mutation), P2X7R-deficient mice or both receptors. The cellular and the humoral responses were lower in the B6/lpr-P2X7KO mouse strain compared to B6, B6-P2X7KO and B6/lpr mouse strains. The antiviral immune response in the B6/lpr mice was lower than in B6 and B6-P2X7KO mice. These results reinforce our hypothesis about the synergistic role of both receptors in the maintaining of T cell homeostasis. Ours results suggest that Fas and P2X7R play their synergistic role in T-cell homeostasis. In collaboration with a team from the University of Taiwan, we sequenced the mRNAs expressed in the spleen and lymph nodes of MRL/lpr mice before and after the onset of the diseases as well as in the B6, B6/lpr, B6 P2X7KO and B6/lpr P2X7KO mouse strains in order to better understand the mechanism triggering the disease and to identify the role of each receptor on the expression of the susceptibility loci.; Mon étude a porté sur le rôle du récepteur purinergique P2X7 (P2X7R) dans les processus physiopathologiques impliqués dans le développement des maladies auto-immunes de type lupique. Les souris MRL/lpr, déficientes en récepteurs d’apoptose Fas (mutation lpr), développent spontanément ces pathologies suite à l’accumulation lymphocytes T pathogéniques CD4−CD8− (DN) B220+ dans les organes lymphoïdes secondaires. Nous avons observé que ces lymphocytes ont également un déficit d’expression en P2X7R à leur surface. Cela nous a amené à postuler que P2X7R pourrait jouer un rôle clé dans l’homéostasie des lymphocytes T et le développement du lupus. Afin de vérifier notre hypothèse, nous avons produit des souris C57BL/6J (B6) déficientes simultanément pour Fas (lpr) et P2X7R (P2X7KO). Ces souris présentent une accumulation massive de lymphocytes T DN B220+ et des titres très élevés en auto-anticorps et en cytokines proinflammatoires ce qui n’est pas le cas pour les souris B6 simples mutantes lpr ou P2X7KO confirmant pour la première fois l’implication de P2X7R dans l’homéostasie des lymphocytes T, en synergie avec le récepteur Fas. Les lymphocytes T DN pathogéniques responsables de la lymphoaccumulation sont issues majoritairement de la sous populations des lymphocytes T CD8+. L’inflammation chronique présente chez les souris B6/lpr P2X7KO induit l’activation de l’ensemble des populations lymphocytaires T CD4+ et CD8+ naïves conduisant à l’accumulation de lymphocytes T Effecteurs/Mémoires : EM et CM et atteignent parfois le stade exhausted PD1+TIM3+. Ces cellules accumulées CD4+, CD8+ et DN B220+ ont une capacité de réactivation réduite. Ce biais fonctionnel et phénotypique a été confirmé en comparant la réponse immunitaire adaptative anti-adénovirus entre des souris déficientes en Fas et/ou P2X7R. Les réponses cellulaires et humorales sont moins importantes dans les souris B6/lpr P2X7KO que B6, B6-P2X7KO. Ces réponses antivirales sont intermédiaires dans les souris B6/lpr. L’ensemble de ces résultats renforcent notre hypothèse sur le rôle synergique des récepteurs Fas et P2X7R dans l’homéostasie des lymphocytes T. Le taux d’apoptose induit par l’activation des récepteurs Fas ou P2X7R séparément est moins important dans les lymphocytes T CD8+ par rapport au lymphocytes T CD4+. La synergie Fas-P2X7R serait donc nécessaire pour l’homéostasie des lymphocytes T CD8+. Afin de préciser les mécanismes à l’origine de la maladie et d’identifier l’influence de chaque récepteur sur l’expression des loci de susceptibilité, nous avons séquencé les ARNm exprimés dans la rate et les ganglions lymphatiques des souris MRL/lpr avant et après le développement de l’auto-immunité ainsi que chez les souris B6, B6/lpr, B6 P2X7KO et B6/lpr P2X7KO.

Published
2018

13. Caractérisation d'anticorps neutralisants réagissant avec le segment des acides aminés 213-224 de la galectine-9 humaine

Author

Claire Lhuillier, Clément Barjon, Valentin Baloche, Toshiro Niki, Aurore Gelin, Rami Mustapha, Laetitia Claër, Sylviane Hoos, Yoichi Chiba, Masaki Ueno, Mitsuomi Hirashima, Ming Wei, Olivier Morales, Bertrand Raynal, Nadira Delhem, Olivier Dellis, Pierre Busson, Signalisation, noyaux et innovations en cancérologie (UMR8126), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Kagawa University [Japan], Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), H-Immune Therapeutics [Paris], Biophysique Moléculaire (Plate-forme), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Cellvax, École nationale vétérinaire d'Alfort (ENVA), Intéractions cellulaires et physiopathologie hépathique (Orsay, Essonne) UMRS 1174 (ICPH ), Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by Idex Saclay - Satt Saclay, Prematuration Grant 2015, https://www.satt-paris-saclay.fr, and BMS Foundation for Immuno-Oncology- Grant 2016-2017, http://fondation-bms.fr/. Several authors were employed by commercial companies: Cellvax (CL, CB, MW)

Subjects
MESH: T-Lymphocytes/metabolism, MESH: Apoptosis/drug effects, MESH: Biological Transport, [SDV]Life Sciences [q-bio], Galectins, T-Lymphocytes, MESH: T-Lymphocytes/drug effects, MESH: Galectins/adverse effects, lcsh:Medicine, Lactose, MESH: Galectins/immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Apoptosis, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Phosphatidylserines, MESH: Antibodies, Neutralizing/pharmacology, Antibodies, Epitopes, Jurkat Cells, Mice, MESH: T-Lymphocytes/cytology, MESH: Jurkat Cells, Animals, Humans, MESH: Animals, Flow cytometry, Enzyme-linked immunoassays, lcsh:Science, MESH: Mice, MESH: Antibodies, Monoclonal/pharmacology, Antibody isotypes, MESH: Humans, lcsh:R, MESH: Calcium/metabolism, Antibodies, Monoclonal, Biological Transport, MESH: Epitopes/immunology, Cell staining, Antibodies, Neutralizing, MESH: Galectins/chemistry, Apoptosis T cells, MESH: Immunization, [SDV.IMM]Life Sciences [q-bio]/Immunology, lcsh:Q, Calcium, Immunization, MESH: Phosphatidylserines/metabolism
Abstract

International audience; Extra-cellular galectin-9 (gal-9) is an immuno-modulatory protein with predominant immuno-suppressive effects. Inappropriate production of gal-9 has been reported in several human malignancies and viral diseases like nasopharyngeal, pancreatic and renal carcinomas, metastatic melanomas and chronic active viral hepatitis. Therefore therapeutic antibodies neutralizing extra-cellular gal-9 are expected to contribute to immune restoration in these pathological conditions. Two novel monoclonal antibodies targeting gal-9-Gal-Nab 1 and 2-have been produced and characterized in this study. We report a protective effect of Gal-Nab1 and Gal-Nab2 on the apoptotic cell death induced by gal-9 in primary T cells. In addition, they inhibit late phenotypic changes observed in peripheral T cells that survive gal-9-induced apoptosis. Gal-Nab1 and Gal-Nab2 bind nearly identical, overlapping linear epi-topes contained in the 213-224 amino-acid segments of gal-9. Nevertheless, they have some distinct functional characteristics suggesting that their three-dimensional epitopes are distinct. These differences are best demonstrated when gal-9 is applied on Jurkat cells where Gal-Nab1 is less efficient than Gal-Nab2 in the prevention of apoptotic cell death. In addition, Gal-Nab1 stimulates non-lethal phosphatidylserine translocation at the plasma membrane and calcium mobilization triggered by gal-9 in these cells. Both Gal-Nab1 and 2 cross-react with murine gal-9. They bind its natural as well as its recombinant form. This cross-species recognition will be an advantage for their assessment in pre-clinical tumor models.

Published
2018

14. Variations in Cellular Responses of Mouse T Cells to Adenosine-5′-Triphosphate Stimulation Do Not Depend on P2X7 Receptor Expression Levels but on Their Activation and Differentiation Stage

Author

Hanaa Safya, Amine Mellouk, Julie Legrand, Sylvain M. Le Gall, Mohcine Benbijja, Colette Kanellopoulos-Langevin, Jean M. Kanellopoulos, Pierre Bobé, Intéractions cellulaires et physiopathologie hépathique (Orsay, Essonne) UMRS 1174 (ICPH ), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 (UP11), Institut André Lwoff - Biologie intégrée de la cellule, virus et cancer (IALBICVC), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Régulation de la réponse immune, infection VIH-1 et autoimmunité, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11), and SERRE, Marie-Claude

Subjects
0301 basic medicine, lcsh:Immunologic diseases. Allergy, Pore Forming Cytotoxic Proteins, Programmed cell death, [SDV]Life Sciences [q-bio], Immunology, Stimulation, Lymphocyte Activation, T-Lymphocytes, Regulatory, CD62L shedding, Immunophenotyping, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, regulatory T lymphocyte, Adenosine Triphosphate, Downregulation and upregulation, Cell Movement, Immunology and Allergy, Animals, Receptor, Original Research, Mice, Knockout, CD39, Immunity, Cellular, Chemistry, Effector, pore formation, Cell Differentiation, Forkhead Transcription Factors, Phosphatidylserine, Purinergic signalling, Acquired immune system, Flow Cytometry, Cell biology, [SDV] Life Sciences [q-bio], Mice, Inbred C57BL, 030104 developmental biology, cell death, Hyaluronan Receptors, Gene Expression Regulation, phosphatidyslerine exposure, CD73, Leukocyte Common Antigens, Receptors, Purinergic P2X7, lcsh:RC581-607, P2X7, 030215 immunology
Abstract

International audience; A previous report has shown that regulatory T cells (Treg) were markedly more sensitive to adenosine-5'-triphosphate (ATP) than conventional T cells (Tconv). Another one has shown that Tregs and CD45RBlowTconvs, but not CD45RBhighTconvs, displayed similar high sensitivity to ATP. We have previously reported that CD45RBlowTconvs expressing B220/CD45RABC molecules in a pre-apoptotic stage are resistant to ATP stimulation due to the loss of P2X7 receptor (P2X7R) membrane expression. To gain a clearer picture on T-cell sensitivity to ATP, we have quantified four different cellular activities triggered by ATP in mouse T cells at different stages of activation/differentiation, in correlation with levels of P2X7R membrane expression. P2X7R expression significantly increases on Tconvs during differentiation from naive CD45RBhighCD44lowto effector/memory CD45RBlowCD44highstage. Maximum levels of upregulation are reached on recently activated CD69+naive and memory Tconvs. Ectonucleotidases CD39 and CD73 expression levels increase in parallel with those of P2X7R. Recently activated CD69+CD45RBhighCD44lowTconvs, although expressing high levels of P2X7R, fail to cleave homing receptor CD62L after ATP treatment, but efficiently form pores and externalize phosphatidylserine (PS). In contrast, naive CD45RBhighCD44lowTconvs cleave CD62L with high efficiency although they express a lower level of P2X7, thus suggesting that P2X7R levels are not a limiting factor for signaling ATP-induced cellular responses. Contrary to common assumption, P2X7R-mediated cellular activities in mouse Tconvs are not triggered in an all-or-none manner, but depend on their stage of activation/differentiation. Compared to CD45RBlowTconvs, CD45RBlowFoxp3+Tregs show significantly higher levels of P2X7R membrane expression and of sensitivity to ATP as evidenced by their high levels of CD62L shedding, pore formation and PS externalization observed after ATP treatment. In summary, the different abilities of ATP-treated Tconvs to form pore or cleave CD62L depending on their activation and differentiation state suggests that P2X7R signaling varies according to the physiological role of T convs during antigen activation in secondary lymphoid organs or trafficking to inflammatory sites.

Published
2018

15. The Shigella type III effector IpgD recodes Ca 2+ signals during invasion of epithelial cells

Author

Ceren Simsek, Christophe Erneux, Benjamin Wacquier, Alexandre Lehman, Daniel I Aguilar, Philippe J. Sansonetti, Laurence Arbibe, Sylviane Boucherie, Kevin Denis, Guy Tran Van Nhieu, Chun Hui Sun, Geneviève Dupont, Cesar Valencia-Gallardo, Laurent Combettes, Jost Enninga, Nathalie Carayol, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Intéractions cellulaires et physiopathologie hépathique (Orsay, Essonne) UMRS 1174 (ICPH ), Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Chronobiologie Théorique [Brussels, Belgium], Université libre de Bruxelles (ULB), Interdisciplinary Research Institute [Brussels, Belgium] (IRIBHM), Dynamique des Interactions Hôte-Pathogène - Dynamics of Host-Pathogen Interactions, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Pathogénie microbienne moléculaire, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Chaire Microbiologie et Maladies infectieuses, Collège de France (CdF (institution)), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution)), The work was supported by the ANR grants MITOPATHO and PATHIMMUN, grant from Tournesol program No. 31268YG, and grants from the Labex Memolife and PSL IDEX Shigaforce. CHS is a recipient of a PhD grant from the China Scholarship Council. DA is a recipient of a CONACYT grant and Labex Memolife. CV‐G was a recipient of the PSL IDEX grant. NC is a recipient of a Marie‐Curie IRG grant. BW and GD are Research Fellow and Research Director at the Belgian F.R.S.‐F.N.R.S., respectively. This work was supported by the Fonds de la Recherche Scientifique‐FNRS under Grant No. J0043.14 and by the Fonds David and Alice Van Buuren. JE was supported by an ERC Starting ('Rupteffects' No. 261166) and a Consolidator Grant ('Endosubvert' No. 682809). LC, GD, and GTVN are recipients of a WBI‐France Exchange Program (Wallonie‐Bruxelles International, Fonds de la Recherche Scientifique, Ministère Français des Affaires étrangères et européennes, Ministère de l'Enseignement supérieur et de la Recherche dans le cadre des Partenariats Hubert Curien)., ANR-12-BSV3-0017,MITOPATHO,Rôle des mitochondries durant l'invasion des cellules par les bactéries Listeria et Shigella(2012), ANR-10-MIDI-0007,PATHIMMUN,Les pathogènes nous enseignent de nouvelles stratégies antiinflammatoires(2010), ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), European Project: 261166,EC:FP7:ERC,ERC-2010-StG_20091118,RUPTEFFECTS(2011), European Project: 682809,EndoSubvert(2017), Langlais, Laurence, BLANC - Rôle des mitochondries durant l'invasion des cellules par les bactéries Listeria et Shigella - - MITOPATHO2012 - ANR-12-BSV3-0017 - BLANC - VALID, MECANISMES INTEGRES DE L'INFLAMMATION - Les pathogènes nous enseignent de nouvelles stratégies antiinflammatoires - - PATHIMMUN2010 - ANR-10-MIDI-0007 - MI2 - VALID, Initiative d'excellence - Paris Sciences et Lettres - - PSL2010 - ANR-10-IDEX-0001 - IDEX - VALID, Revealing the mechanism of host membrane rupture by invasive pathogens and its role in triggering the immune response - RUPTEFFECTS - - EC:FP7:ERC2011-03-01 - 2016-02-29 - 261166 - VALID, Common mechanisms of host membrane trafficking subversion by intracellular pathogens to rupture bacterial containing vacuoles - EndoSubvert - 2017-01-01 - 2021-12-31 - 682809 - VALID, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Collège de France - Chaire Microbiologie et Maladies infectieuses, and Université Paris sciences et lettres (PSL)

Subjects
0301 basic medicine, MESH: Signal Transduction, MESH: Shigella flexneri, MESH: Calpain, Cell, Regulator, [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Shigella flexneri, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], MESH: Bacterial Proteins, biology, Effector, General Neuroscience, Calpain, Articles, Cell biology, Phosphotransferases (Alcohol Group Acceptor), medicine.anatomical_structure, MESH: Calcium, Host-Pathogen Interactions, Second messenger system, MESH: Phosphoric Monoester Hydrolases, IpgD, medicine.symptom, calpain, Signal Transduction, Programmed cell death, MESH: Dysentery, Bacillary, Inflammation, General Biochemistry, Genetics and Molecular Biology, MESH: Cell Adhesion, 03 medical and health sciences, Bacterial Proteins, Cell Adhesion, medicine, Humans, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Cell adhesion, Molecular Biology, Dysentery, Bacillary, calcium, MESH: Humans, General Immunology and Microbiology, talin, MESH: Host-Pathogen Interactions, MESH: Phosphotransferases (Alcohol Group Acceptor), Phosphoric Monoester Hydrolases, 030104 developmental biology, MESH: HeLa Cells, biology.protein, Shigella, HeLa Cells
Abstract

The role of second messengers in the diversion of cellular processes by pathogens remains poorly studied despite their importance. Among these, Ca 2+ virtually regulates all known cell processes, including cytoskeletal reorganization, inflammation, or cell death pathways. Under physiological conditions, cytosolic Ca 2+ increases are transient and oscillatory, defining the so‐called Ca 2+ code that links cell responses to specific Ca 2+ oscillatory patterns. During cell invasion, Shigella induces atypical local and global Ca 2+ signals. Here, we show that by hydrolyzing phosphatidylinositol‐(4,5)bisphosphate, the Shigella type III effector IpgD dampens inositol‐(1,4,5)trisphosphate (InsP 3 ) levels. By modifying InsP 3 dynamics and diffusion, IpgD favors the elicitation of long‐lasting local Ca 2+ signals at Shigella invasion sites and converts Shigella ‐induced global oscillatory responses into erratic responses with atypical dynamics and amplitude. Furthermore, IpgD eventually inhibits InsP 3 ‐dependent responses during prolonged infection kinetics. IpgD thus acts as a pathogen regulator of the Ca 2+ code implicated in a versatility of cell functions. Consistent with this function, IpgD prevents the Ca 2+ ‐dependent activation of calpain, thereby preserving the integrity of cell adhesion structures during the early stages of infection.

Published
2017

16. Experimental assessment of the safety and potential efficacy of high irradiance photostimulation of brain tissues

Author

Claire Martin, Frédéric Pain, Suhan Senova, Stéphane Palfi, Antoine Chaillet, Chih-Chieh Chiang, Ilona Scisniak, Isabelle Doignon, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Groupe Henri Mondor-Albert Chenevier, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Imagerie et Modélisation en Neurobiologie et Cancérologie (IMNC (UMR_8165)), Université Paris-Sud - Paris 11 (UP11)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), University of Warsaw (UW), National Tsing Hua University [Hsinchu] (NTHU), Intéractions cellulaires et physiopathologie hépathique (Orsay, Essonne) UMRS 1174 (ICPH ), Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire des signaux et systèmes (L2S), Université Paris-Sud - Paris 11 (UP11)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), ANR-13-JS03-0006,SYNCHNEURO,Théorie de la commande pour la synchronisation neuronale: modélisation à partir de données l'optogénétique, et alteration boucle-fermée des oscillations cérébrales pathologiques(2013), Laboratoire des signaux et systèmes ( L2S ), Université Paris-Sud - Paris 11 ( UP11 ) -CentraleSupélec-Centre National de la Recherche Scientifique ( CNRS ), Imagerie et Modélisation en Neurobiologie et Cancérologie ( IMNC ), Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de Physique Nucléaire et de Physique des Particules du CNRS ( IN2P3 ) -Université Paris-Sud - Paris 11 ( UP11 ), PAIN, FREDERIC, Jeunes Chercheuses et Jeunes Chercheurs - Théorie de la commande pour la synchronisation neuronale: modélisation à partir de données l'optogénétique, et alteration boucle-fermée des oscillations cérébrales pathologiques - - SYNCHNEURO2013 - ANR-13-JS03-0006 - JC - VALID, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)

Subjects
0301 basic medicine, Hot Temperature, [SPI.OPTI] Engineering Sciences [physics]/Optics / Photonic, Light, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Irradiance, Biology, Optogenetics, Photostimulation, [ SDV.IB.MN ] Life Sciences [q-bio]/Bioengineering/Nuclear medicine, Translational Research, Biomedical, 03 medical and health sciences, 0302 clinical medicine, In vivo, medicine, Animals, Rats, Wistar, ComputingMilieux_MISCELLANEOUS, [ SDV.IB.IMA ] Life Sciences [q-bio]/Bioengineering/Imaging, Cerebral Cortex, Neurons, Multidisciplinary, High irradiance, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Neuromodulation (medicine), Electrophysiology, 030104 developmental biology, medicine.anatomical_structure, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, Cerebral cortex, [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SPI.OPTI]Engineering Sciences [physics]/Optics / Photonic, [ SPI.OPTI ] Engineering Sciences [physics]/Optics / Photonic, Erratum, 030217 neurology & neurosurgery, Biomedical engineering
Abstract

Optogenetics is widely used in fundamental neuroscience. Its potential clinical translation for brain neuromodulation requires a careful assessment of the safety and efficacy of repeated, sustained optical stimulation of large volumes of brain tissues. This study was performed in rats and not in non-human primates for ethical reasons. We studied the spatial distribution of light, potential damage, and non-physiological effects in vivo, in anesthetized rat brains, on large brain volumes, following repeated high irradiance photo-stimulation. We generated 2D irradiance and temperature increase surface maps based on recordings taken during optical stimulation using irradiance and temporal parameters representative of common optogenetics experiments. Irradiances of 100 to 600 mW/mm2 with 5 ms pulses at 20, 40, and 60 Hz were applied during 90 s. In vivo electrophysiological recordings and post-mortem histological analyses showed that high power light stimulation had no obvious phototoxic effects and did not trigger non-physiological functional activation. This study demonstrates the ability to illuminate cortical layers to a depth of several millimeters using pulsed red light without detrimental thermal damages.

Published
2017
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17. Another example of enzymatic promiscuity: the polyphosphate kinase of Streptomyces lividans is endowed with phospholipase D activity

Author

Catherine Esnault, Denis Leiber, Claire Toffano-Nioche, Zahra Tanfin, Marie-Joelle Virolle, Métabolisme Energétique des Streptomyces ( MESMIC ), Département Microbiologie ( Dpt Microbio ), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Sciences de la vie ( UFR 927 ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), INSERM U1063, Séquence, Structure et Fonction des ARN ( SSFA ), Département Biologie des Génomes ( DBG ), IBAIC, INSERM U1174, Institut National de la Santé et de la Recherche Médicale ( INSERM ), Métabolisme Energétique des Streptomyces (MESMIC), Département Microbiologie (Dpt Microbio), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), UPMC - UFR Sciences de la vie (UFR 927 ), Université Pierre et Marie Curie - Paris 6 (UPMC), Stress Oxydant et Pathologies Métaboliques (SOPAM), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Séquence, Structure et Fonction des ARN (SSFA), Département Biologie des Génomes (DBG), Intéractions cellulaires et physiopathologie hépathique (Orsay, Essonne) UMRS 1174 (ICPH ), Institut National de la Santé et de la Recherche Médicale (INSERM), University Paris-Sud, University Pierre and Marie Curie, CNRS, Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Institut de Biologie Intégrative de la Cellule (I2BC), and Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay

Subjects
0301 basic medicine, Protein Conformation, Promiscuous enzyme, [SDV]Life Sciences [q-bio], Amino Acid Motifs, 030106 microbiology, Phosphatidic Acids, Biology, Applied Microbiology and Biotechnology, Choline, 03 medical and health sciences, Polyphosphate kinase, chemistry.chemical_compound, Phosphatidylcholine, Phospholipase D, Phospholipase D activity, chemistry.chemical_classification, Phosphotransferases (Phosphate Group Acceptor), [ SDV ] Life Sciences [q-bio], Kinase, Hydrolysis, Cell Membrane, General Medicine, Phosphatidic acid, Lipid droplets, enzymes and coenzymes (carbohydrates), 030104 developmental biology, Membrane, Enzyme, chemistry, Biochemistry, Phosphatidylcholines, Streptomyces lividans, lipids (amino acids, peptides, and proteins), Biotechnology
Abstract

International audience; Polyphosphate kinases (PPK) from different bacteria, including that of Streptomyces lividans, were shown to contain the typical HKD motif present in phospholipase D (PLD) and showed structural similarities to the latter. This observation prompted us to investigate the PLD activity of PPK of S. lividans, in vitro. The ability of PPK to catalyze the hydrolysis of phosphatidylcholine (PC), the PLD substrate, was assessed by the quantification of [3H]phosphatidic acid (PA) released from [3H]PC-labeled ELT3 cell membranes. Basal cell membrane PLD activity as well as GTPγS-activated PLD activity was higher in the presence than in absence of PPK. After abolition of the basal PLD activity of the membranes by heat or tryptic treatment, the addition of PPK to cell membranes was still accompanied by an increased production of PA demonstrating that PPK also bears a PLD activity. PLD activity of PPK was also assessed by the production of choline from hydrolysis of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) in the presence of the Amplex Red reagent and compared to two commercial PLD enzymes. These data demonstrated that PPK is endowed with a weak but clearly detectable PLD activity. The question of the biological signification, if any, of this enzymatic promiscuity is discussed.

Published
2016

18. Inherited IL-18BP deficiency in human fulminant viral hepatitis

Author

Emmanuelle Jouanguy, Julie Bruneau, Yoon Seung Lee, Jean-Laurent Casanova, Lazaro Lorenzo-Diaz, Mohammad Kabbani, Eleftherios Michailidis, Serkan Belkaya, Scott Drutman, Laurent Abel, Soraya Boucherit, Cecilia B. Korol, Mylène Sebagh, Vivien Béziat, Aurélie Cobat, Ype P. de Jong, Bertrand Boisson, Nicholas Hernandez, Charles M. Rice, Paul Bastard, Jean-François Emile, Eric Vivier, Emmanuel Jacquemin, Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'anatomie et cythologie pathologique, CHU Necker - Enfants Malades [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, Département de Pathologie [Villejuif], Hôpital Paul Brousse, Physiopathogenèse et Traitement des Maladies du Foie [Villejuif], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11), Intéractions cellulaires et physiopathologie hépathique (Orsay, Essonne) UMRS 1174 (ICPH ), Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire épidémiologie et oncogénèse des tumeurs digestives, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Génétique Humaine des Maladies Infectieuses (Inserm U980), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Laboratory of Virology and Infectious Disease [New York], Rockefeller University [New York], Université Paris Descartes - Paris 5 (UPD5), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Physiopathogénèse et Traitement des Maladies du Foie, and Hôpital Paul Brousse-Université Paris-Saclay

Subjects
0301 basic medicine, Hepatitis, Mutation, business.industry, Fulminant, Immunology, medicine.disease, medicine.disease_cause, Virology, 3. Good health, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Immunity, 030220 oncology & carcinogenesis, Immunology and Allergy, Medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Interleukin 18, business, Viral hepatitis, Exome sequencing, IL18BP
Abstract

Fulminant viral hepatitis (FVH) is a devastating and unexplained condition that strikes otherwise healthy individuals during primary infection with common liver-tropic viruses. We report a child who died of FVH upon infection with hepatitis A virus (HAV) at age 11 yr and who was homozygous for a private 40-nucleotide deletion in IL18BP, which encodes the IL-18 binding protein (IL-18BP). This mutation is loss-of-function, unlike the variants found in a homozygous state in public databases. We show that human IL-18 and IL-18BP are both secreted mostly by hepatocytes and macrophages in the liver. Moreover, in the absence of IL-18BP, excessive NK cell activation by IL-18 results in uncontrolled killing of human hepatocytes in vitro. Inherited human IL-18BP deficiency thus underlies fulminant HAV hepatitis by unleashing IL-18. These findings provide proof-of-principle that FVH can be caused by single-gene inborn errors that selectively disrupt liver-specific immunity. They also show that human IL-18 is toxic to the liver and that IL-18BP is its antidote.

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