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1. Oral Administration of Lactobacillus helveticus LA401 and Lactobacillus gasseri LA806 Combination Attenuates Oesophageal and Gastrointestinal Candidiasis and Consequent Gut Inflammation in Mice

Author

Hélène Authier, Marie Salon, Mouna Rahabi, Bénédicte Bertrand, Claude Blondeau, Sarah Kuylle, Sophie Holowacz, and Agnès Coste

Subjects
gastrointestinal candidiasis, gut inflammation, macrophages, Lactobacillus gasseri, Lactobacillus helveticus, probiotic, Biology (General), QH301-705.5
Abstract

Candida albicans is an opportunistic pathogen that causes mucosal gastrointestinal (GI) candidiasis tightly associated with gut inflammatory status. The emergence of drug resistance, the side effects of currently available antifungals and the high frequency of recurrent candidiasis indicate that new and improved therapeutics are needed. Probiotics have been suggested as a useful alternative for the management of candidiasis. We demonstrated that oral administration of Lactobacillus gasseri LA806 alone or combined with Lactobacillus helveticus LA401 in Candida albicans-infected mice decrease the Candida colonization of the oesophageal and GI tract, highlighting a protective role for these strains in C. albicans colonization. Interestingly, the probiotic combination significantly modulates the composition of gut microbiota towards a protective profile and consequently dampens inflammatory and oxidative status in the colon. Moreover, we showed that L. helveticus LA401 and/or L. gasseri LA806 orient macrophages towards a fungicidal phenotype characterized by a C-type lectin receptors signature composed of Dectin-1 and Mannose receptor. Our findings suggest that the use of the LA401 and LA806 combination might be a promising strategy to manage GI candidiasis and the inflammation it causes by inducing the intrinsic antifungal activities of macrophages. Thus, the probiotic combination is a good candidate for managing GI candidiasis by inducing fungicidal functions in macrophages while preserving the GI integrity by modulating the microbiota and inflammation.

Published
2021
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2. P17, an Original Host Defense Peptide from Ant Venom, Promotes Antifungal Activities of Macrophages through the Induction of C-Type Lectin Receptors Dependent on LTB4-Mediated PPARγ Activation

Author

Khaddouj Benmoussa, Hélène Authier, Mélissa Prat, Mohammad AlaEddine, Lise Lefèvre, Mouna Chirine Rahabi, José Bernad, Agnès Aubouy, Elsa Bonnafé, Jérome Leprince, Bernard Pipy, Michel Treilhou, and Agnès Coste

Subjects
Macrophages, host defense peptide, antimicrobial peptides, Candida albicans, C-type lectin receptors, arachidonic acid metabolism, Immunologic diseases. Allergy, RC581-607
Abstract

Despite the growing knowledge with regard to the immunomodulatory properties of host defense peptides, their impact on macrophage differentiation and on its associated microbicidal functions is still poorly understood. Here, we demonstrated that the P17, a new cationic antimicrobial peptide from ant venom, induces an alternative phenotype of human monocyte-derived macrophages (h-MDMs). This phenotype is characterized by a C-type lectin receptors (CLRs) signature composed of mannose receptor (MR) and Dectin-1 expression. Concomitantly, this activation is associated to an inflammatory profile characterized by reactive oxygen species (ROS), interleukin (IL)-1β, and TNF-α release. P17-activated h-MDMs exhibit an improved capacity to recognize and to engulf Candida albicans through the overexpression both of MR and Dectin-1. This upregulation requires arachidonic acid (AA) mobilization and the activation of peroxisome proliferator-activated receptor gamma (PPARγ) nuclear receptor through the leukotriene B4 (LTB4) production. AA/LTB4/PPARγ/Dectin-1-MR signaling pathway is crucial for P17-mediated anti-fungal activity of h-MDMs, as indicated by the fact that the activation of this axis by P17 triggered ROS production and inflammasome-dependent IL-1β release. Moreover, we showed that the increased anti-fungal immune response of h-MDMs by P17 was dependent on intracellular calcium mobilization triggered by the interaction of P17 with pertussis toxin-sensitive G-protein-coupled receptors on h-MDMs. Finally, we also demonstrated that P17-treated mice infected with C. albicans develop less severe gastrointestinal infection related to a higher efficiency of their macrophages to engulf Candida, to produce ROS and IL-1β and to kill the yeasts. Altogether, these results identify P17 as an original activator of the fungicidal response of macrophages that acts upstream PPARγ/CLRs axis and offer new immunomodulatory therapeutic perspectives in the field of infectious diseases.

Published
2017
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3. Bioactive fish collagen peptides weaken intestinal inflammation by orienting colonic macrophages phenotype through mannose receptor activation

Author

Mouna Rahabi, Marie Salon, Christelle Bruno-Bonnet, Mélissa Prat, Godefroy Jacquemin, Khaddouj Benmoussa, Mohamad Alaeddine, Mélissa Parny, José Bernad, Bénédicte Bertrand, Yannick Auffret, Pascale Robert-Jolimaître, Laurent Alric, Hélène Authier, and Agnès Coste

Subjects
Inflammation, Nutrition and Dietetics, Colon, Macrophages, Dextran Sulfate, Anti-Inflammatory Agents, Medicine (miscellaneous), Colitis, Inflammatory Bowel Diseases, Antioxidants, Mice, Inbred C57BL, Disease Models, Animal, Mice, Phenotype, Animals, Humans, Collagen, Peptides, Mannose, Mannose Receptor
Abstract

Purpose Particular interest is now given to the potential of dietary supplements as alternative non-pharmacological approaches in intestinal inflammation handling. In this aim, this study evaluates the efficiency of fish collagen peptides, Naticol®Gut, on colonic inflammation. Methods Wild type and Mannose receptor-deficient in the myeloid lineage C57BL/6 mice were administered with Dextran Sodium Sulfate (DSS), Naticol®Gut, DSS, and Naticol®Gut or only water for 4 or 8 days. Inflammatory status was evaluated by establishing macroscopic and microscopic scores, by measuring cytokine and calprotectin production by ELISA and the myeloperoxidase activity by chemiluminescence. Colonic macrophages were phenotyped by measuring mRNA levels of specific markers of inflammation and oxidative status. Colonic immune populations and T-cell activation profiles were determined by flow cytometry. Mucosa-associated gut microbiota assessment was undertaken by qPCR. The phenotype of human blood monocytes from inflammatory bowel disease (IBD) subjects was characterized by RT-qPCR and flow cytometry and their oxidative activity by chemiluminescence. Results Naticol®Gut-treated DSS mice showed attenuated colonic inflammation compared to mice that were only exposed to DSS. Naticol®Gut activity was displayed through its ability to orient the polarization of colonic macrophage towards an anti-inflammatory and anti-oxidant phenotype after its recognition by the mannose receptor. Subsequently, Naticol®Gut delivery modulated CD4 T cells in favor of a Th2 response and dampened CD8 T-cell activation. This immunomodulation resulted in an intestinal eubiosis. In human monocytes from IBD subjects, the treatment with Naticol®Gut also restored an anti-inflammatory and anti-oxidant phenotype. Conclusion Naticol®Gut acts as a protective agent against colitis appearing as a new functional food and an innovative and complementary approach in gut health.

Published
2022

4. Circulating CD14high CD16low intermediate blood monocytes as a biomarker of ascites immune status and ovarian cancer progression

Author

Godefroy Jacquemin, Bettina Couderc, Augustin Le Naour, Gwenael Ferron, Kimberley Coulson, Jean-Marc Barret, Hélène Leray, Hélène Authier, Maha Ayyoub, Jean-Pierre Delord, Lea Lemaitre, Isabelle Tabah-Fisch, Jean-François Prost, Mouna Rahabi, Alejandra Martinez, Agnès Coste, Mélissa Prat, Fanny Lemée, and Laurence Gladieff

Subjects
Oncology, Male, Cancer Research, medicine.medical_specialty, medicine.medical_treatment, Immunology, Short Report, Lipopolysaccharide Receptors, Monocytes, Immune system, biomarkers, tumor, Internal medicine, Ascites, medicine, Tumor Microenvironment, Immunology and Allergy, Humans, RC254-282, Pharmacology, Tumor microenvironment, business.industry, Receptors, IgG, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Immunosuppression, Immunotherapy, medicine.disease, immunity, macrophages, Tumor progression, Disease Progression, Molecular Medicine, Biomarker (medicine), Female, medicine.symptom, business, Ovarian cancer
Abstract

BackgroundBesides the interest of an early detection of ovarian cancer, there is an urgent need for new predictive and prognostic biomarkers of tumor development and cancer treatment. In healthy patients, circulating blood monocytes are typically subdivided into classical (85%), intermediate (5%) and non-classical (10%) populations. Although these circulating monocyte subsets have been suggested as biomarkers in several diseases, few studies have investigate their potential as a predictive signature for tumor immune status,tumor growth and treatment adaptation.MethodsIn this study, we used a homogeneous cohort of 28 chemotherapy-naïve patients with ovarian cancer to evaluate monocyte subsets as biomarkers of the ascites immunological status. We evaluated the correlations between circulating monocyte subsets and immune cells and tumor burden in peritoneal ascites. Moreover, to validate the use of circulating monocyte subsets tofollow tumor progression and treatment response, we characterized blood monocytes from ovarian cancer patients included in a phase 1 clinical trial at baseline and following murlentamab treatment.ResultsWe demonstrate here a robust expansion of the intermediate blood monocytes (IBMs) in ovarian cancer patients. We establish a significant positive correlation between IBM percentage and tumor–associate macrophages with a CCR2high/CD163high/CD206high/CD86lowprofile. Moreover, IBM expansion is associated with a decreased effector/regulatory T-cell ratio in ascites and with the presence of soluble immunosuppressive mediators. We also establish that IBM proportion positively correlates with the peritoneum tumor burden. Finally, the study of IBMs in patients with ovarian cancer under immunotherapy during the phase clinical trial supports IBMs to follow the evolution of tumor development and the treatment adaptation.ConclusionsThis study, which links IBM level with immunosuppression and tumor burden in peritoneum, identifies IBMs as apotential predictive signature of ascites immune status and as a biomarker ofovarian cancer development and treatment response.Trial registration numberEudraCT: 2015-004252-22NCT02978755.

Published
2020

5. IL13-Mediated Dectin-1 and Mannose Receptor Overexpression Promotes Macrophage Antitumor Activities through Recognition of Sialylated Tumor Cells

Author

François Couderc, Camille Alric, Christophe Dardenne, Bettina Couderc, Bruno Ségui, José Bernad, Lise Lefèvre, Mélissa Prat, Bernard Pipy, Etienne Meunier, Agnès Coste, Patricia Balard, Laurent Alric, Hélène Authier, Véréna Poinsot, Mohamad Alaeddine, Valérie Gouazé-Andersson, Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD), Interactions moléculaires et réactivité chimique et photochimique (IMRCP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Nutergia, This research was supported by a grant from CIFRE-Association Nationale de la Recherche et de la Technologie (ANRT) awarded to M. Alaeddine (2012/1416) and from the Nutergia Laboratory (to A. Coste and B. Pipy), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT)-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Fédération de Recherche Fluides, Energie, Réacteurs, Matériaux et Transferts (FERMAT), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), BIBAC - Chimie analytique et interactions biomolécules - matière molle biomimétique (BIBAC), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie de Toulouse (ICT), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées, Polarisation des Macrophages et Récepteurs Nucléaires dans les Pathologies Inflammatoires et Infectieuses, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR50, Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques (IP-TPT), Service de Santé des Armées-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD), Institut de Recherche en Santé Digestive (IRSD ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Astrophysique de Marseille (LAM), Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Aix Marseille Université (AMU)-Centre National d'Études Spatiales [Toulouse] (CNES), Institut Claudius Regaud, CRLCC Institut Claudius Regaud, Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Service de Santé des Armées, Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), and Aix Marseille Université (AMU)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Cancer Research, Necrosis / immunology, Mice Knockout, T-Lymphocytes, Receptor expression, Gene Expression, Macrophages / immunology, Mice, 0302 clinical medicine, Interleukin-13 / genetics, N-Acetylneuraminic Acid / metabolism, Neoplasms, Arginase / metabolism, Lectins, Mannose-Binding Lectins / genetics, Receptors, Macrophage, Cytotoxic T cell, Neoplasms / etiology, Receptor, Cytotoxicity, ComputingMilieux_MISCELLANEOUS, Neoplasms / metabolism, Mice, Knockout, Interleukin-13, Tumor, Chemistry, Prognosis, 3. Good health, 030220 oncology & carcinogenesis, Signal transduction, Mannose Receptor, Mannose receptor, C-Type / metabolism, Signal Transduction, Immunology, Interleukin-13 / metabolism, Receptors, Cell Surface, Cell Line, Necrosis, 03 medical and health sciences, Cell Surface / genetics, C-Type / genetics, Cell Line, Tumor, Macrophages / metabolism, Animals, Humans, [CHIM]Chemical Sciences, Lectins, C-Type, Mannose-Binding Lectins / metabolism, Cell Surface / metabolism, Neoplasms / pathology, Arginase, Macrophages, T-Lymphocytes / immunology, Reactive Oxygen Species / metabolism, N-Acetylneuraminic Acid, Neoplasms / mortality, Mannose-Binding Lectins, Cell culture, Cancer research, Necrosis / genetics, Reactive Oxygen Species, T-Lymphocytes / metabolism, 030215 immunology
Abstract

Macrophage-mediated cytotoxicity is controlled by surface receptor expression and activation. Despite the numerous studies documenting the role of macrophage C-type lectin receptors (CLR) in pathogen elimination, little is known about their contribution to antitumor responses. Here, we report that IL13 inhibits T-cell lymphoma and ovarian adenocarcinoma development in tumor-bearing mice through the conversion of tumor-supporting macrophages to cytotoxic effectors, characterized by a CLR signature composed of dectin-1 and mannose receptor (MR). We show that dectin-1 and MR are critical for the recognition of tumor cells through sialic acid–specific glycan structure on their surface and for the subsequent activation of macrophage tumoricidal response. Finally, we validated that IL13 antitumor effect mediated by dectin-1 and MR overexpression on macrophages can extend to various types of human tumors. Therefore, these results identify these CLRs as potential targets to promote macrophage antitumor response and represent an attractive approach to elicit tumor-associated macrophage tumoricidal properties.

Published
2019

6. Oral Administration of Lactobacillus helveticus LA401 and Lactobacillus gasseri LA806 Combination Attenuates Oesophageal and Gastrointestinal Candidiasis and Consequent Gut Inflammation in Mice

Author

Sophie Holowacz, Bénédicte Bertrand, Agnès Coste, Hélène Authier, Sarah Kuylle, Marie Salon, Mouna Rahabi, Claude Blondeau, Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), PiLeJe Laboratoire, and Genibio [Lorp-Sentaraille]

Subjects
Microbiology (medical), C-type lectin receptor, [SDV]Life Sciences [q-bio], Inflammation, Plant Science, Gut flora, Lactobacillus gasseri, Lactobacillus helveticus, Article, Microbiology, law.invention, 03 medical and health sciences, Probiotic, 0302 clinical medicine, law, medicine, Candida albicans, lcsh:QH301-705.5, Ecology, Evolution, Behavior and Systematics, mannose receptor, 030304 developmental biology, 0303 health sciences, biology, business.industry, biology.organism_classification, Corpus albicans, macrophages, lcsh:Biology (General), 030220 oncology & carcinogenesis, gut inflammation, dectin-1, medicine.symptom, business, gastrointestinal candidiasis, probiotic, Mannose receptor
Abstract

Candida albicans is an opportunistic pathogen that causes mucosal gastrointestinal (GI) candidiasis tightly associated with gut inflammatory status. The emergence of drug resistance, the side effects of currently available antifungals and the high frequency of recurrent candidiasis indicate that new and improved therapeutics are needed. Probiotics have been suggested as a useful alternative for the management of candidiasis. We demonstrated that oral administration of Lactobacillus gasseri LA806 alone or combined with Lactobacillus helveticus LA401 in Candida albicans-infected mice decrease the Candida colonization of the oesophageal and GI tract, highlighting a protective role for these strains in C. albicans colonization. Interestingly, the probiotic combination significantly modulates the composition of gut microbiota towards a protective profile and consequently dampens inflammatory and oxidative status in the colon. Moreover, we showed that L. helveticus LA401 and/or L. gasseri LA806 orient macrophages towards a fungicidal phenotype characterized by a C-type lectin receptors signature composed of Dectin-1 and Mannose receptor. Our findings suggest that the use of the LA401 and LA806 combination might be a promising strategy to manage GI candidiasis and the inflammation it causes by inducing the intrinsic antifungal activities of macrophages. Thus, the probiotic combination is a good candidate for managing GI candidiasis by inducing fungicidal functions in macrophages while preserving the GI integrity by modulating the microbiota and inflammation.

Published
2021

7. Protolichesterinic acid derivatives: α-methylene-γ-lactones as potent dual activators of PPARγ and Nrf2 transcriptional factors

Author

Isabelle Rouaud, Agnès Coste, Anne-Cécile Le Lamer, Bernard Pipy, Nicolas Gouault, Joël Boustie, Hélène Authier, Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), and Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD)

Subjects
PPARγ, NF-E2-Related Factor 2, Stereochemistry, Protolichesterinic acid, Clinical Biochemistry, Pharmaceutical Science, Antineoplastic Agents, Biochemistry, Nrf2, Lactones, Mice, Structure-Activity Relationship, chemistry.chemical_compound, 4-Butyrolactone, Cell Line, Tumor, Drug Discovery, Animals, Humans, Moiety, Potency, [CHIM]Chemical Sciences, Methylene, Cytotoxicity, Molecular Biology, Transcription factor, Cell Proliferation, Dose-Response Relationship, Drug, Molecular Structure, Macrophages, Organic Chemistry, respiratory system, 3. Good health, PPAR gamma, α-Methylene-γ-lactones, chemistry, Michael reaction, Molecular Medicine, Organic synthesis, Drug Screening Assays, Antitumor, Signal transduction, Michael acceptor
Abstract

International audience; PPARγ and Nrf2 are important transcriptional factors involved in many signaling pathways, especially in the anti-infectious response of macrophages. Compounds bearing a Michael acceptor moiety are well known to activate such transcriptional factors, we thus evaluated the potency of α,β-unsaturated lactones synthesized using fluorous phase organic synthesis. Compounds were first screened for their cytotoxicity in order to select lactones for PPARγ and Nrf2 activation evaluation. Among them, two α-methylene-γ-lactones were identified as potent dual activators of PPARγ and Nrf2 in macrophages.

Published
2014

8. The C-type Lectin Receptors Dectin-1, MR, and SIGNR3 Contribute Both Positively and Negatively to the Macrophage Response to Leishmania infantum

Author

Carine Duval, Johan Auwerx, Christophe Dardenne, Jean Loup Lemesre, Alexis Valentin, Hélène Authier, Bernard Pipy, Etienne Meunier, David Olagnier, Lise Lefèvre, Olivier Neyrolles, Geanncarlo Lugo-Villarino, Agnès Coste, José Bernad, Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques (IP-TPT), Service de Santé des Armées-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Focal Area Infection Biology, Biozentrum, University of Basel (Unibas), Division of Infectious Diseases, University of South Florida (USF), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona (UB), Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Laboratoire de la Signalisation et de la Différenciation des Macrophages, Institution Louis Bugnard, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Service de Santé des Armées, Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Signal Transduction, MESH: Mannose-Binding Lectins / metabolism, [SDV]Life Sciences [q-bio], Interleukin-1beta, MESH: Leishmaniasis, Visceral / immunology, Antigens, CD/metabolism, Macrophages/immunology, MESH: Mice, Knockout, MESH: Antigens, CD / metabolism, MESH: Protein-Tyrosine Kinases / metabolism, Caspase 1/metabolism, Mice, 0302 clinical medicine, MESH: Leishmania infantum / immunology, MESH: Caspase 1 / metabolism, C-type lectin, MESH: RNA, Small Interfering, MESH: Interleukin-1beta / antagonists & inhibitors, Macrophage, Immunology and Allergy, MESH: Animals, MESH: Leishmaniasis, Visceral / parasitology, MESH: Receptors, Cell Surface / metabolism, Leishmania infantum, RNA, Small Interfering, Receptor, MESH: NADPH Oxidases / metabolism, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, 0303 health sciences, Arachidonic Acid, biology, Effector, Caspase 1, Intracellular Signaling Peptides and Proteins, Protein-Tyrosine Kinases, MESH: Macrophages / immunology, 3. Good health, Cell biology, MESH: Leukotriene B4 / antagonists & inhibitors, Infectious Diseases, Intracellular Signaling Peptides and Proteins/metabolism, NADPH Oxidases/metabolism, Leishmaniasis, Visceral, [SDV.IMM]Life Sciences [q-bio]/Immunology, RNA Interference, Signal transduction, Interleukin-1beta/antagonists & inhibitors, Mannose receptor, Mannose Receptor, Signal Transduction, MESH: Cells, Cultured, MESH: Reactive Oxygen Species / metabolism, Immunology, MESH: RNA Interference, Receptors, Cell Surface, Leukotriene B4, Arachidonic Acid/metabolism, MESH: Syk Kinase, 03 medical and health sciences, Antigens, CD, Reactive Oxygen Species/metabolism, MESH: Mice, Inbred C57BL, parasitic diseases, MESH: Arachidonic Acid / metabolism, Animals, Humans, Syk Kinase, Lectins, C-Type, Lectins, C-Type/immunology, MESH: Interleukin-1beta / metabolism, Receptors, Cell Surface/metabolism, Mannose-Binding Lectins/metabolism, MESH: Mice, 030304 developmental biology, MESH: Humans, Leishmania infantum/immunology, Macrophages, NADPH Oxidases, biology.organism_classification, Leishmania, MESH: Mannose Receptor, Leishmaniasis, Visceral/immunology, Protein-Tyrosine Kinases/metabolism, MESH: Lectins, C-Type / metabolism, Mice, Inbred C57BL, MESH: Lectins, C-Type / immunology, Mannose-Binding Lectins, Leukotriene B4/antagonists & inhibitors, Reactive Oxygen Species, MESH: Intracellular Signaling Peptides and Proteins / metabolism, 030215 immunology
Abstract

International audience; Macrophages act as the primary effector cells during Leishmania infection through production of reactive oxygen species (ROS) and interleukin-1β (IL-1β). However, how macrophage-killing mechanisms are activated during Leishmania-macrophage interactions is poorly understood. Here, we report that the macrophage response against Leishmania infantum in vivo is characterized by an M2b-like phenotype and C-type lectin receptors (CLRs) signature composed of Dectin-1, mannose receptor (MR), and the DC-SIGN homolog SIGNR3 expression. Dectin-1 and MR were crucial for the microbicidal response as indicated by the fact that they activated Syk-p47phox and arachidonic acid (AA)-NADPH oxidase signaling pathways, respectively, needed for ROS production and also triggered Syk-coupled signaling for caspase-1-induced IL-1β secretion. In contrast, SIGNR3 has divergent functions during Leishmania infantum pathogenesis; this CLR favored parasite resilience through inhibition of the LTB4-IL-1β axis. These pathways also operated during infection of primary human macrophages. Therefore, our study promotes CLRs as potential targets for treatment, diagnosis, and prevention of visceral leishmaniasis.

Published
2013

9. IL-13 attenuates gastrointestinal candidiasis in normal and immunodeficient RAG-2(-/-) mice via peroxisome proliferator-activated receptor-gamma activation

Author

Cédric Filipe, José Bernad, Johan Auwerx, Victorine Douin-Echinard, Jean-François Arnal, Patricia Balard, Amandine Gales, Agnès Coste, Bernard Pipy, Hélène Authier, Jean-Claude Lepert, Céline Lagane, Marie-Denise Linas, Peney, Maité, Laboratoire de la Signalisation et de la Différenciation des Macrophages, Institution Louis Bugnard, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Clinique de la Souris (ICS), and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I

Subjects
Phagocyte, Gastrointestinal Diseases, Immunology, Peroxisome proliferator-activated receptor, Receptors, Cell Surface, Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Ligands, Microbiology, Rosiglitazone, Mice, Cell Movement, Candida albicans, medicine, Immunology and Allergy, Macrophage, Animals, Lectins, C-Type, Receptor, Cecum, chemistry.chemical_classification, Mice, Knockout, Interleukin-13, Macrophages, Candidiasis, Immunologic Deficiency Syndromes, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, biology.organism_classification, Corpus albicans, DNA-Binding Proteins, PPAR gamma, medicine.anatomical_structure, Mannose-Binding Lectins, chemistry, Interleukin 13, Female, Thiazolidinediones, Mannose receptor, Mannose Receptor
Abstract

We recently demonstrated that in vitro peroxisome proliferator-activated receptor-γ (PPARγ) activation of mouse peritoneal macrophages by IL-13 or PPARγ ligands promotes uptake and killing of Candida albicans through mannose receptor overexpression. In this study, we demonstrate that i.p. treatment of immunocompetent and immunodeficient (RAG-2−/−) mice with natural and synthetic PPARγ-specific ligands or with IL-13 decreases C. albicans colonization of the gastrointestinal (GI) tract 8 days following oral infection with the yeast. We also showed that Candida GI infection triggers macrophage recruitment in cecum mucosa. These mucosal macrophages, as well as peritoneal macrophages, overexpress the mannose receptor after IL-13 and rosiglitazone treatments. The treatments promote macrophage activation against C. albicans as suggested by the increased ability of peritoneal macrophages to phagocyte C. albicans and to produce reactive oxygen intermediates after yeast challenge. These effects on C. albicans GI infection and on macrophage activation are suppressed by treatment of mice with GW9662, a selective PPARγ antagonist, and are reduced in PPARγ+/− mice. Overall, these data demonstrate that IL-13 or PPARγ ligands attenuate C. albicans infection of the GI tract through PPARγ activation and hence suggest that PPARγ ligands may be of therapeutic value in esophageal and GI candidiasis in immunocompromised patients.

Published
2008

10. IL-13 induces expression of CD36 in human monocytes through PPARgamma activation

Author

Johan Auwerx, Pierre Chambon, Jean Paul Séguéla, Jean François Magnaval, David Olagnier, Céline Lagane, Françoise Benoit-Vical, Béatrice Desvergne, Jean Claude Lepert, Daniel Metzger, Antoine Berry, Hélène Authier, Bernard Pipy, Patricia Balard, Walter Wahli, Agnès Coste, Laboratoire d'Informatique, de Modélisation et d'optimisation des Systèmes (LIMOS), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Sigma CLERMONT (Sigma CLERMONT)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure des Mines de St Etienne, Laboratoire d'Astrophysique de Marseille (LAM), Aix Marseille Université (AMU)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Physique Théorique d'Orsay [Orsay] (LPT), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Anthropobiologie (LA), École des hautes études en sciences sociales (EHESS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL)-Université de Lausanne (UNIL), Institut de Biologie Animale, Université de Lausanne (UNIL), Laboratoire de la Signalisation et de la Différenciation des Macrophages, Institution Louis Bugnard, Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Université d'Auvergne - Clermont-Ferrand I (UdA)-SIGMA Clermont (SIGMA Clermont)-Ecole Nationale Supérieure des Mines de St Etienne (ENSM ST-ETIENNE)-Centre National de la Recherche Scientifique (CNRS), École des hautes études en sciences sociales (EHESS)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), Université de Lausanne = University of Lausanne (UNIL), SIGMA Clermont (SIGMA Clermont)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Ecole Nationale Supérieure des Mines de St Etienne-Centre National de la Recherche Scientifique (CNRS)-Université Blaise Pascal - Clermont-Ferrand 2 (UBP), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, and Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)

Subjects
CD36 Antigens, Erythrocytes, Phospholipases A/antagonists & inhibitors, CD36, Plasmodium falciparum/physiology, Peroxisome proliferator-activated receptor, Gene Expression, Endogeny, Monocytes, CD36 Antigens/genetics, Prostaglandin D2/analogs & derivatives, Mice, 0302 clinical medicine, Macrophages/drug effects, Organophosphonates/pharmacology, Immunology and Allergy, DNA/metabolism, Anilides, Thiazolidinediones/pharmacology, Enzyme Inhibitors, Receptor, Macrophages, Peritoneal/drug effects, chemistry.chemical_classification, Enzyme Inhibitors/pharmacology, 0303 health sciences, Interleukin-13, Prostaglandin D2, Transfection, Protein Binding/drug effects, 3. Good health, Cell biology, Anilides/pharmacology, Biochemistry, 030220 oncology & carcinogenesis, Interleukin 13, Protein Binding, Interleukin-13/pharmacology, Phagocytosis/drug effects, Immunology, Plasmodium falciparum, Organophosphonates, Erythrocytes/drug effects, Arachidonic Acids, Gene Expression/drug effects, Biology, Phospholipases A, Rosiglitazone, Hypoglycemic Agents/pharmacology, 03 medical and health sciences, Phagocytosis, Arachidonic Acids/pharmacology, Monocytes/drug effects, Cell Line, Tumor, parasitic diseases, Hypoglycemic Agents, Animals, Humans, Scavenger receptor, 030304 developmental biology, PPAR gamma/agonists, Macrophages, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, DNA, PPAR gamma, Phospholipases A2, chemistry, Nuclear receptor, biology.protein, Macrophages, Peritoneal, Thiazolidinediones
Abstract

The class B scavenger receptor CD36 is a component of the pattern recognition receptors on monocytes that recognizes a variety of molecules. CD36 expression in monocytes depends on exposure to soluble mediators. We demonstrate here that CD36 expression is induced in human monocytes following exposure to IL-13, a Th2 cytokine, via the peroxisome proliferator-activated receptor (PPAR)gamma pathway. Induction of CD36 protein was paralleled by an increase in CD36 mRNA. The PPARgamma pathway was demonstrated using transfection of a PPARgamma expression plasmid into the murine macrophage cell line RAW264.7, expressing very low levels of PPARgamma, and in peritoneal macrophages from PPARgamma-conditional null mice. We also show that CD36 induction by IL-13 via PPARgamma is dependent on phospholipase A2 activation and that IL-13 induces the production of endogenous 15-deoxy-Delta12,14-prostaglandin J2, an endogenous PPARgamma ligand, and its nuclear localization in human monocytes. Finally, we demonstrate that CD36 and PPARgamma are involved in IL-13-mediated phagocytosis of Plasmodium falciparum-parasitized erythrocytes. These results reveal a novel role for PPARgamma in the alternative activation of monocytes by IL-13, suggesting that endogenous PPARgamma ligands, produced by phospholipase A2 activation, could contribute to the biochemical and cellular functions of CD36.

Published
2007

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