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1. Leishmania infantum exploits the anti-ferroptosis effects of Nrf2 to escape cell death in macrophages

Author

Clément Blot, Mathilde Lavernhe, Geanncarlo Lugo-Villarino, Kimberley Coulson, Marie Salon, Margot Tertrais, Rémi Planès, Karin Santoni, Hélène Authier, Godefroy Jacquemin, Mouna Rahabi, Mélissa Parny, Isabelle Raymond Letron, Etienne Meunier, Lise Lefèvre, and Agnès Coste

Subjects
CP: Immunology, CP: Microbiology, Biology (General), QH301-705.5
Abstract

Summary: Macrophages are major host cells for the protozoan Leishmania parasite. Depending on their activation state, they either contribute to the detection and elimination of Leishmania spp. or promote parasite resilience. Here, we report that the activation of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) in macrophages plays a pivotal role in the progression of Leishmania infantum infection by controlling inflammation and redox balance of macrophages. We also highlight the involvement of the NOX2/reactive oxygen species (ROS) axis in early Nrf2 activation and, subsequently, prostaglandin E2 (PGE2)/EP2r signaling in the sustenance of Nrf2 activation upon infection. Moreover, we establish a ferroptosis-like process within macrophages as a cell death program of L. infantum and the protective effect of Nrf2 in macrophages against L. infantum death. Altogether, these results identify Nrf2 as a critical factor for the susceptibility of L. infantum infection, highlighting Nrf2 as a promising pharmacological target for the development of therapeutic approaches for the treatment of visceral leishmaniasis.

Published
2024
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2. Generation of functionally active resident macrophages from adipose tissue by 3D cultures

Author

Adèle Arlat, Marie-Laure Renoud, Jean Nakhle, Miguel Thomas, Jessica Fontaine, Emmanuelle Arnaud, Cédric Dray, Hélène Authier, Paul Monsarrat, Agnès Coste, Louis Casteilla, Marielle Ousset, and Béatrice Cousin

Subjects
resident macrophage, macrophage subpopulation, adipose tissue, bone marrow, 3D culture, metabolism, Immunologic diseases. Allergy, RC581-607
Abstract

IntroductionWithin adipose tissue (AT), different macrophage subsets have been described, which played pivotal and specific roles in upholding tissue homeostasis under both physiological and pathological conditions. Nonetheless, studying resident macrophages in-vitro poses challenges, as the isolation process and the culture for extended periods can alter their inherent properties.MethodsStroma-vascular cells isolated from murine subcutaneous AT were seeded on ultra-low adherent plates in the presence of macrophage colony-stimulating factor. After 4 days of culture, the cells spontaneously aggregate to form spheroids. A week later, macrophages begin to spread out of the spheroid and adhere to the culture plate.ResultsThis innovative three-dimensional (3D) culture method enables the generation of functional mature macrophages that present distinct genic and phenotypic characteristics compared to bone marrow–derived macrophages. They also show specific metabolic activity and polarization in response to stimulation, but similar phagocytic capacity. Additionally, based on single-cell analysis, AT-macrophages generated in 3D culture mirror the phenotypic and functional traits of in-vivo AT resident macrophages.DiscussionOur study describes a 3D in-vitro system for generating and culturing functional AT-resident macrophages, without the need for cell sorting. This system thus stands as a valuable resource for exploring the differentiation and function of AT-macrophages in vitro in diverse physiological and pathological contexts.

Published
2024
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3. PPARγ activation modulates the balance of peritoneal macrophage populations to suppress ovarian tumor growth and tumor-induced immunosuppression

Author

Hélène Authier, Agnès Coste, Gwenael Ferron, Mélissa Prat, Augustin Le Naour, Kimberley Coulson, Godefroy Jacquemin, Mouna Chirine Rahabi, Jean-Pierre Delord, Bettina Couderc, Clément Blot, Mathilde Romano, Marie-Laure Renoud, Mohamad AlaEddine, Khaddouj Benmoussa, Marie Salon, Mélissa Parny, and Lise Lefèvre

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Background Ovarian adenocarcinoma (OVAD) frequently metastasizes to the peritoneal cavity and manifests by the formation of ascites, which constitutes a tumor-promoting microenvironment. In the peritoneal cavity, two developmentally, phenotypically and functionally distinct macrophage subsets, immunocompetent large peritoneal macrophages (LPM) and immunosuppressive small peritoneal macrophages (SPM), coexist. Because peroxisome proliferator-activated receptor γ (PPARγ) is a critical factor participating in macrophage differentiation and cooperates with CCAAT/enhancer binding protein β (C/EBPβ), a transcription factor essential for SPM-to-LPM differentiation, PPARγ could be also involved in the regulation of SPM/LPM balance and could be a promising therapeutic target.Methods To evaluate the 15(S)-hydroxyeicosatetraenoic acid (HETE), a PPARγ endogenous ligand, impact on ovarian tumor growth, we intraperitoneally injected 15(S)-HETE into a murine ovarian cancer model. This experimental model consists in the intraperitoneally injection of ID8 cells expressing luciferase into syngeneic C57BL/6 female mice. This ID8 orthotopic mouse model is a well-established experimental model of end-stage epithelial OVAD. Tumor progression was monitored using an in vivo imaging system. Peritoneal immune cells in ascites were analyzed by flow cytometry and cell sorting. To determine whether the impact of 15(S)-HETE in tumor development is mediated through the macrophages, these cells were depleted by injection of liposomal clodronate. To further dissect how 15(S)-HETE mediated its antitumor effect, we assessed the tumor burden in tumor-bearing mice in which the PPARγ gene was selectively disrupted in myeloid-derived cells and in mice deficient of the recombination-activating gene Rag2. Finally, to validate our data in humans, we isolated and treated macrophages from ascites of individuals with OVAD.Results Here we show, in the murine experimental model of OVAD, that 15(S)-HETE treatment significantly suppresses the tumor growth, which is associated with the differentiation of SPM into LPM and the LPM residency in the peritoneal cavity. We demonstrate that C/EBPβ and GATA6 play a central role in SPM-to-LPM differentiation and in LPM peritoneal residence through PPARγ activation during OVAD. Moreover, this SPM-to-LPM switch is associated with the increase of the effector/regulatory T-cell ratio. Finally, we report that 15(S)-HETE attenuates immunosuppressive properties of human ovarian tumor-associated macrophages from ascites.Conclusion Altogether, these results promote PPARγ as a potential therapeutic target to restrain OVAD development and strengthen the use of PPARγ agonists in anticancer therapy.

Published
2023
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4. Synergistic Effects of Licorice Root and Walnut Leaf Extracts on Gastrointestinal Candidiasis, Inflammation and Gut Microbiota Composition in Mice

Author

Hélène Authier, Valérie Bardot, Lucile Berthomier, Bénédicte Bertrand, Claude Blondeau, Sophie Holowacz, and Agnès Coste

Subjects
candidiasis, gut inflammation, licorice, plant extract, prebiotic, walnut, Microbiology, QR1-502
Abstract

ABSTRACT Candida albicans is an opportunistic pathogen that causes gastrointestinal (GI) candidiasis closely associated with intestinal inflammation and dysbiosis. Drug resistance, side effects of available antifungal agents, and the high recurrence of candidiasis highlight the need for new treatments. We investigated the effects of hydroethanolic extracts of licorice root (LRE) and walnut leaf (WLE) on GI colonization by C. albicans, colon inflammation, and gut microbiota composition in C57BL/6 female mice. Oral administration of LRE and WLE alone or in combination once daily for 12 days before C. albicans infection and then for 5 days after infection significantly reduced the level of C. albicans in the feces of gastrointestinal infected mice as well as colonization of the GI tract, both extracts showing robust antifungal activity. Although total bacterial content was unaffected by the extracts (individually or combined), the abundance of protective bacteria, such as Bifidobacterium spp. and Faecalibacterium prausnitzii, increased with the combination, in contrast to that of certain pathobiont bacteria, which decreased. Interestingly, the combination induced a more robust decrease in the expression of proinflammatory genes than either extract alone. The anti-inflammatory activity of the combination was further supported by the reciprocal increase in the expression of anti-inflammatory cytokines and the significant decrease in enzymes involved in the synthesis of proinflammatory eicosanoids and oxidative stress. These findings suggest that LRE and WLE have synergistic effects and that the LRE/WLE combination could be a good candidate for limiting GI candidiasis and associated inflammation, likely by modulating the composition of the gut microbiota. IMPORTANCE The adverse effects and emergence of resistance of currently available antifungals and the high recurrence of candidiasis prompt the need for alternative and complementary strategies. We demonstrated that oral administration of hydroethanolic extracts of licorice root (LRE) and walnut leaf (WLE) separately or in combination significantly reduced the colonization of the gastrointestinal (GI) tract by C. albicans, highlighting a robust antifungal activity of these plant extracts. Interestingly, our data indicate a correlation between LRE and WLE consumption, in particular the combination, and a shift within the gut microbiome toward a protective profile, a decrease in colonic inflammation and prooxidant enzymes, suggesting a synergistic effect. This study highlights the significant prebiotic potential of the LRE/WLE combination and suggests that the health benefits are due, at least in part, to their ability to modulate the gut microbiota, reduce inflammation and oxidative stress, and protect against opportunistic infection.

Published
2022
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5. 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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6. 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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7. Data from IL13-Mediated Dectin-1 and Mannose Receptor Overexpression Promotes Macrophage Antitumor Activities through Recognition of Sialylated Tumor Cells

Author

Agnès Coste, Bernard Pipy, Bettina Couderc, François Couderc, Patricia Balard, Bruno Segui, Laurent Alric, José Bernad, Christophe Dardenne, Camille Alric, Lise Lefèvre, Etienne Meunier, Hélène Authier, Valérie Gouazé-Andersson, Véréna Poinsot, Mélissa Prat, and Mohamad Alaeddine

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
2023

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

Author

Agnès Coste, Bernard Pipy, Bettina Couderc, François Couderc, Patricia Balard, Bruno Segui, Laurent Alric, José Bernad, Christophe Dardenne, Camille Alric, Lise Lefèvre, Etienne Meunier, Hélène Authier, Valérie Gouazé-Andersson, Véréna Poinsot, Mélissa Prat, and Mohamad Alaeddine

Abstract

Primer sequences

Published
2023

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

Author

Agnès Coste, Bernard Pipy, Bettina Couderc, François Couderc, Patricia Balard, Bruno Segui, Laurent Alric, José Bernad, Christophe Dardenne, Camille Alric, Lise Lefèvre, Etienne Meunier, Hélène Authier, Valérie Gouazé-Andersson, Véréna Poinsot, Mélissa Prat, and Mohamad Alaeddine

Abstract

Figure S1-Figure S8

Published
2023

10. 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

11. 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

13. 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

14. Divergent Roles for Macrophage C-Type Lectin Receptors, Dectin-1 and Mannose Receptors, in Inflammatory Bowel Diseases

Author

Bernard Pipy, Mohamad Alaeddine, Delphine Bonnet, Sylvain Kirzin, Hélène Authier, Godefroy Jacquemin, Mouna Rahabi, Marie Danjoux, Johan Auwerx, Lise Lefèvre, Agnès Aubouy, Khaddouj Benmoussa, Agnès Coste, Etienne Meunier, Bénédicte Bertrand, Laurent Alric, Philippe Batigne, and Mélissa Prat

Subjects
education.field_of_study, Innate immune system, Leukotriene B4, business.industry, Monocyte, Population, Inflammation, medicine.disease, digestive system diseases, chemistry.chemical_compound, medicine.anatomical_structure, chemistry, Immunology, medicine, Macrophage, Colitis, medicine.symptom, education, business, Mannose receptor
Abstract

Colonic macrophages are considered as major effectors of inflammatory bowel diseases (IBD), and the control of gut inflammation through C-type lectin receptors is an emerging concept. We show that during colitis the loss of Dectin-1 prevents intestinal inflammation, while the lack of MR exacerbates it. A marked increase in Dectin-1 expression in DSS-exposed MR-deficient mice, support the critical contribution of Dectin-1 in the development of colitis. Dectin-1 is crucial for Ly6ChighCCR2high monocyte population enrichment in the blood and their recruitment to inflamed colon as precursors of M1 inflammatory macrophages. Dectin-1 also promotes inflammasome-dependent IL-1β secretion through the leukotriene B4 production. Interestingly, the colonic inflammation is associated with a concomitant overexpression of Dectin-1/CCL2/LTA4H and a down-regulation of MR on macrophages from IBD patients. Thus, MR and Dectin-1 on macrophage are important mucosal inflammatory regulators during IBD. Finally, this study offers breakthroughs on the mechanism may contribute to the pathogenesis of IBD in humans.

Published
2019

15. 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

16. Le P17, un nouveau peptide antimicrobien, favorise l’activité antifongique des macrophages via l’induction des récepteurs Mannose et Dectine-1 et contribue à la résolution d’une candidose digestive expérimentale

Author

Jérôme Leprince, José Bernad, Hélène Authier, Agnès Coste, Mouna Rahabi, Elsa Bonnafé, Mohammad Alaeddine, Michel Treilhou, Bernard Pipy, Mélissa Prat, Khaddouj Benmoussa, Lise Lefèvre, 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), Biochimie et Toxicologie des Substances Bioactives (BTSB), Institut national universitaire Champollion [Albi] (INUC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Plate-Forme de Recherche en Imagerie Cellulaire de Haute-Normandie (PRIMACEN), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Université de Toulouse (UT)-Université de Toulouse (UT), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-High-tech Research Infrastructures for Life Sciences (HeRacLeS), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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 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), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Infectious Diseases, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology
Abstract

Article présenté dans un congrès à Toulouse les 30 et 31 mars 2017.; International audience; Malgré la connaissance croissante en ce qui concerne les propriétés immunomodulatrices des peptides antimicrobiens (AMP), leur impact sur la différenciation des macrophages et sur les fonctions microbicides associées est encore mal compris. Dans ce travail nous mettons en évidence l’activité immunomodulatrice du P17, un nouveau peptide antimicrobien isolé à partir du venin de fourmis. Nous montrons que ce peptide oriente la différenciation des macrophages dérivés de monocytes humains (h-MDMs) vers un phénotype particulier caractérisé à la fois par la surexpression des récepteurs mannose (RM) et Dectine-1, deux récepteurs lectine de type C (CLRs), et par une signature pro-inflammatoire. Dans cet état d’activation, les h-MDMs présentent une capacité accrue à reconnaître et internaliser C. albicans. Ces h-MDMs acquièrent aussi des fonctions fongicides puissantes via l’activation de la NADPH oxydase, enzyme nécessaire à la production d’espèces réactives de l’oxygène (ROS) et de l’inflammasome essentiel à la libération d’IL-1β. Nous démontrons également que la surexpression des récepteurs RM et Dectine-1 nécessite la mobilisation de l’acide arachidonique et la synthèse du leucotriène B4 (LTB4), essentiel à l’activation du récepteur nucléaire PPARg. Ainsi, la voie de signalisation LTB4/PPARg/MR-Dectine-1 est essentielle pour l’activité antifongique des h-MDMs activés par le P17. Enfin, nous avons également démontré in vivo que les souris traitées par le P17 infectées développent une infection gastro-intestinale à C. albicans moins sévère que les souris non traitées. En accord avec ces résultats, les macrophages isolés des souris traitées par le P17 ont une meilleure capacité à phagocyter C. albicans, à produire des ROS et à éliminer les levures ex vivo. Ces travaux mettent en évidence le P17 comme un activateur original de la réponse fongicide des macrophages et offrent de nouvelles perspectives thérapeutiques immunomodulatrices dans le domaine des maladies infectieuses.

Published
2017

17. The IKK complex contributes to the induction of autophagy

Author

Ezgi Tasdemir, Alfredo Criollo, Alain Israël, Amena Ben Younes, Maximilien Tailler, Guido Kroemer, Eugenia Morselli, Oliver Kepp, Daniela De Stefano, Hélène Authier, Laurence Zitvogel, Maria Chiara Maiuri, Laura Senovilla, Gérard Pierron, Ilio Vitale, Shensi Shen, Véronique Baud, Nicolas F. Delahaye, Sergio Lavandero, Francis Harper, Lorenzo Galluzzi, Antoine Tesniere, Criollo, A, Senovilla, L, Authier, H, Maiuri, MARIA CHIARA, Morselli, E, Vitale, I, Kepp, O, Tasdemir, E, Galluzzi, L, Shen, S, Tailler, M, Delahaye, N, Tesniere, A, DE STEFANO, Daniela, Younes, Ab, Harper, F, Pierron, G, Lavandero, S, Zitvogel, L, Israel, A, Baud, V, and Kroemer, G.

Subjects
Mice, Transgenic, IκB kinase, Biology, BAG3, environment and public health, Article, General Biochemistry, Genetics and Molecular Biology, Mice, chemistry.chemical_compound, Autophagy, Animals, Humans, CHUK, Molecular Biology, Transcription factor, Cells, Cultured, General Immunology and Microbiology, General Neuroscience, NF-kappa B, NF-κB, NFKB1, I-kappa B Kinase, Cell biology, Mice, Inbred C57BL, enzymes and coenzymes (carbohydrates), chemistry, Multiprotein Complexes, NIH 3T3 Cells, biological phenomena, cell phenomena, and immunity, Signal transduction, HeLa Cells, Signal Transduction
Abstract

In response to stress, cells start transcriptional and transcription-independent programs that can lead to adaptation or death. Here, we show that multiple inducers of autophagy, including nutrient depletion, trigger the activation of the IKK (IkappaB kinase) complex that is best known for its essential role in the activation of the transcription factor NF-kappaB by stress. Constitutively active IKK subunits stimulated autophagy and transduced multiple signals that operate in starvation-induced autophagy, including the phosphorylation of AMPK and JNK1. Genetic inhibition of the nuclear translocation of NF-kappaB or ablation of the p65/RelA NF-kappaB subunit failed to suppress IKK-induced autophagy, indicating that IKK can promote the autophagic pathway in an NF-kappaB-independent manner. In murine and human cells, knockout and/or knockdown of IKK subunits (but not that of p65) prevented the induction of autophagy in response to multiple stimuli. Moreover, the knockout of IKK-beta suppressed the activation of autophagy by food deprivation or rapamycin injections in vivo, in mice. Altogether, these results indicate that IKK has a cardinal role in the stimulation of autophagy by physiological and pharmacological stimuli.

Published
2009

18. IKK phosphorylates RelB to modulate its promoter specificity and promote fibroblast migration downstream of TNF receptors

Author

Hélène Authier, Pierre Rivière, Véronique Baud, Emmanuel Derudder, Katy Billot, D Bordereaux, Clara Nahmias, Sylvie Rodrigues-Ferreira, Departamento de Quimica, Universidad Autonoma de Madrid (UAM), and Universidad Autónoma de Madrid (UAM)

Subjects
[SDV]Life Sciences [q-bio], Transcription Factor RelB, IκB kinase, Biology, Receptors, Tumor Necrosis Factor, Fibroblast migration, Mice, Phosphoserine, NF-KappaB Inhibitor alpha, Cell Movement, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Phosphorylation, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Promoter Regions, Genetic, ComputingMilieux_MISCELLANEOUS, Cell Nucleus, Multidisciplinary, Tumor Necrosis Factor-alpha, Kinase, RELB, I-Kappa-B Kinase, [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], Biological Sciences, Fibroblasts, I-kappa B Kinase, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], IκBα, HEK293 Cells, Cancer research, I-kappa B Proteins, Matrix Metalloproteinase 3
Abstract

TNFα is a potent cytokine that plays a critical role in numerous cellular processes, particularly immune and inflammatory responses, programmed cell death, angiogenesis, and cell migration. Thus, understanding the molecular mechanisms that mediate TNFα-induced cellular responses is a crucial issue. It is generally accepted that global DNA binding activity of the NF-κB avian reticuloendotheliosis viral (v-rel) oncogene related B (RelB) subunit is not induced upon TNFα treatment in fibroblasts, despite its TNFα-induced nuclear accumulation. Here, we demonstrate that RelB plays a critical role in promoting fibroblast migration upon prolonged TNFα treatment. We identified the two kinases IκB kinase α (IKKα) and IκB kinase β (IKKβ) as RelB interacting partners whose activation by TNFα promotes RelB phosphorylation at serine 472. Once phosphorylated on serine 472, nuclear RelB dissociates from its interaction with the inhibitory protein IκBα and binds to the promoter of critical migration-associated genes, such as the matrix metallopeptidase 3 (MMP3). Further, we show that RelB serine 472 phosphorylation status controls MMP3 expression and promigration activity downstream of TNF receptors. Our findings provide new insights into the regulation of RelB activity and reveal a novel link between selective NF-κB target gene expression and cellular response in response to TNFα.

Published
2014

19. 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

20. IKK connects autophagy to major stress pathways

Author

Amena BenYounès, Alfredo Criollo, Maximilien Tailler, Shensi Shen, Lorenzo Galluzzi, Alain Israël, Véronique Baud, Nicolas F. Delahaye, Laura Senovilla, Gérard Pierron, Hélène Authier, Maria Chiara Maiuri, Eugenia Morselli, Guido Kroemer, Laurence Zitvogel, Oliver Kepp, Francis Harper, Daniela De Stefano, Antoine Tesniere, Ilio Vitale, Ezgi Tasdemir, Sergio Lavandero, Criollo, A, Senovilla, L, Authier, H, Maiuri, MARIA CHIARA, Morselli, E, Vitale, I, Kepp, O, Tasdemir, E, Galluzzi, L, Shen, S, Tailler, M, Delahaye, N, Tesniere, A, DE STEFANO, Daniela, Younes, Ab, Harper, F, Pierron, G, Lavandero, S, Zitvogel, L, Israel, A, Baud, V, and Kroemer, G.

Subjects
Autophagy, AMPK, Context (language use), Cell Biology, IκB kinase, Biology, Models, Biological, I-kappa B Kinase, Cell biology, Stress, Physiological, Cytoplasm, Animals, Humans, Molecular Biology, Transcription factor, PI3K/AKT/mTOR pathway, Signal Transduction
Abstract

Cells respond to stress by activating cytoplasmic mechanisms as well as transcriptional programs that can lead to adaptation or death. Autophagy represents an important cytoprotective response that is regulated by both transcriptional and transcription-independent pathways. NFkappaB is perhaps the transcription factor most frequently activated by stress and has been ascribed with either pro- or anti-autophagic functions, depending on the cellular context. Our results demonstrate that activation of the IKK (IkappaB kinase) complex, which is critical for the stress-elicited activation of NFkappaB, is sufficient to promote autophagy independent of NFkappaB, and that IKK is required for the optimal induction of autophagy by both physiological and pharmacological autophagic triggers.

Published
2010

21. Cartographie de l’expression des différentes isoenzymes de la monoxyde d’azote synthase dans l’hyperplasie bénigne prostatique

Author

Maxime Thoulouzan, M. Ala Eddine, X. Gamé, Louis Bujan, P. Njomnang Soh, M. Soulié, Nicolas Doumerc, Hélène Authier, Pascal Rischmann, F. Zaidi, P. Roulette, Catherine Mazerolles, E. Huyghe, Agnès Coste, and B. Malavaud

Subjects
Gynecology, medicine.medical_specialty, business.industry, Urology, Medicine, business
Abstract

Objectifs Etudier la repartition des trois monoxide d’azote synthase (NOS) : nNOS, iNOS, eNOS entre les zones peripherique (ZP) et transitionnelle (ZT) chez des patients ayant une hyperplasie benigne prostatique (HBP). Methodes Une etude prospective unicentrique a ete realisee sur les tissus non tumoraux des ZP et ZT de pieces de prostatectomie radicale d’hommes ayant une HBP. Les patients ayant eu des traitements modifiant la structure de la glande ont ete exclus. Une etude de l’expression des 3 isoenzymes a ete menee par qRT-PCR dans chaque zone. L’inflammation histologique aigue et chronique a ete scoree. Chaque patient a repondu en preoperatoire aux questionnaires symptomatiques IPSS, USP et IIEF5. Le critere de jugement principal etait l’expression des differentes NOS au sein de la prostate par qRT-PCR. Resultats Seize des 85 patients ayant eu une prostatectomie totale entre le 01/11/13 et le 01/05/14 ont ete inclus. La qRT-PCR a montre une expression des trois isoenzymes dans la ZP et la ZT. Leur expression etait comparable au sein de la ZT, mais dans la ZP, il existait significativement moins de nNOS que de eNOS (p = 0,0017) et de iNOS (p = 0,0016). Il existait une correlation inverse entre l’expression de eNOS au sein de la ZP et le score IPSS (r = –0,5414), le score de qualite de vie (r = –0,5613) et une correlation positive avec l’IIEF (r = 0,5680). En revanche, aucune difference d’expression des NOS n’a ete trouvee entre la ZP et la ZT, et il n’y avait pas de relation entre expression des NOS et poids prostatique, scores USP dysurie et hyperactivite vesicale. Conclusion Les trois NOS etaient exprimees dans la ZP et la ZT. Dans la ZP, l’expression de la nNOS etait plus faible que celle de eNOS et de iNOS. De plus, il y avait une correlation inverse entre l’expression de eNOS au sein de la ZP et les symptomes urinaires et une correlation positive avec l’IIEF.

Published
2014

22. 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

23. Double-walled carbon nanotubes trigger IL-1β release in human monocytes through Nlrp3 inflammasome activation

Author

Emmanuel Flahaut, Bernard Pipy, David Olagnier, Etienne Meunier, Lise Lefèvre, Maryse Beraud, Christophe Dardenne, José Bernad, Hélène Authier, Agnès Coste, Polarisation des Macrophages et Récepteurs Nucléaires dans les Pathologies Inflammatoires et Infectieuses, Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-IFR50, 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 interuniversitaire de recherche et d'ingenierie des matériaux (CIRIMAT), Centre National de la Recherche Scientifique - CNRS (FRANCE), Institut National Polytechnique de Toulouse - INPT (FRANCE), Institut de Recherche pour le Développement - IRD (FRANCE), Université Toulouse III - Paul Sabatier - UT3 (FRANCE), IFR50-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC), and Institut National Polytechnique de Toulouse - Toulouse INP (FRANCE)

Subjects
Interleukin-1beta/immunology, Double-walled carbon nanotubes, Materials science, Inflammasomes/immunology, Inflammasomes, Phagocytosis, Interleukin-1beta, Biomedical Engineering, Pharmaceutical Science, Medicine (miscellaneous), Médecine humaine et pathologie, Bioengineering, Inflammation, 02 engineering and technology, Carbon nanotube, Monocytes, law.invention, [SPI.MAT]Engineering Sciences [physics]/Materials, 03 medical and health sciences, law, Monocytes/drug effects, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Nlrp3 inflammasome, Materials Testing, medicine, Humans, General Materials Science, Secretion, Inflammation Mediators/immunology, Receptor, Cells, Cultured, 030304 developmental biology, 0303 health sciences, Nanotubes, Carbon, Inflammasome, 021001 nanoscience & nanotechnology, Cell biology, Micro et nanotechnologies/Microélectronique, IL-1β, Human monocytes, Immunology, Molecular Medicine, Efflux, NLRP3 inflammasome activation, medicine.symptom, Inflammation Mediators, 0210 nano-technology, medicine.drug
Abstract

Because of their outstanding physical properties, carbon nanotubes (CNTs) are promising new materials in the field of nanotechnology. It is therefore imperative to assess their adverse effects on human health. Monocytes/macrophages that recognize and eliminate the inert particles constitute the main target of CNTs. In this article, we report our finding that double-walled CNTs (DWCNTs) synergize with Tolllike receptor agonists to enhance IL-1β release in human monocytes. We show that DWCNTs–induced IL-1β secretion is exclusively linked to caspase-1 and to Nlrp3 inflammasome activation in human monocytes. We also establish that this activation requires DWCNTs phagocytosis and potassium efflux, but not reactive oxygen specied (ROS) generation. Moreover, inhibition of lysosomal acidification or cathepsin-B activation reduces DWCNT-induced IL-1β secretion, suggesting that Nlrp3 inflammasome activation occurs via lysosomal destabilization. Thus, DWCNTs present a health hazard due to their capacity to activate Nlrp3 inflammasome, recalling the inflammation caused by asbestos and hence demonstrating that they should be used with caution. From the Clinical Editor: This is a very important biosafety/toxicity study regarding double walled carbon nanotubes. The investigators demonstrate that such nanotubes do represent a health hazard due to their capacity to activate Nlrp3 inflammasome, resembling the inflammation caused by asbestos. While further study of this phenomenon is definitely needed, the above findings clearly suggest that special precautions need to be taken when applying these nanoparticles in human disease research.

Published
2012

24. RelB inhibits cell proliferation and tumor growth through p53 transcriptional activation

Author

D Bordereaux, Emilie Jacque, Katy Billot, Hélène Authier, Véronique Baud, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes, Sorbonne Paris Cité, 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), 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
p53, Transcriptional Activation, Cancer Research, Transcription, Genetic, [SDV]Life Sciences [q-bio], Cell, Transplantation, Heterologous, RelB, Biology, Cell Line, 03 medical and health sciences, Mice, 0302 clinical medicine, Downregulation and upregulation, Growth factor receptor, Neoplasms, Genetics, medicine, Animals, Humans, NF-kB, Molecular Biology, 030304 developmental biology, Cell Proliferation, Mice, Knockout, 0303 health sciences, Gene knockdown, Cell growth, RELB, Transcription Factor RelB, Cell cycle, Up-Regulation, Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, Ectopic expression, Tumor Suppressor Protein p53, Neoplasm Transplantation
Abstract

International audience; The alternative nuclear factor-kappaB (NF-κB) -activation pathway proceeds via inducible p100 processing, leading to the activation of RelB-containing dimers. This pathway is aberrantly activated in several types of tumors; however, a direct role for RelB in the control of cell proliferation is still largely unexplored. Here, we demonstrate that RelB provides cell proliferation-inhibitory signals in murine fibroblasts. In agreement with these results, RelB ectopic expression inhibits xenograft tumor growth in vivo, whereas RelB knockdown enhances it. Significantly, we show that RelB inhibits cell proliferation and tumor growth in a p53-dependent manner. Mechanistic studies indicate that RelB regulates the transcription of the p53 tumor-suppressor gene through direct recruitment to the p53 promoter, thus increasing both p53 protein levels and expression of p53 target genes such as p21. Our findings define a novel link between NF-κB and growth-inhibitory pathways involving the RelB-dependent transcriptional upregulation of p53. Furthermore, they suggest that inhibition of RelB in some tumor types that retain wild-type p53 may diminish rather than improve therapeutic responses.

Published
2012

25. Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors

Author

Frédéric Commo, Sylvie Rusakiewicz, Jean Franãois Emile, Caroline Flament, Jean-Yves Blay, Nicolas Ibrahim, Véronique Minard-Colin, Saadia Kerdine-Römer, Philippe Terrier, Jacques A. Nunès, Cédric Ménard, Pascale Paul, Benedita Rocha, Laurence Zitvogel, Kariman Chaba, Alessandro Moretta, Dominique Valteau-Couanet, Cristina Bottino, Javier Celis Gutierrez, Luc Lyonnet, A. Lecesne, Nathalie Chaput, Stephan Roux, Hélène Authier, Jean Michel Coindre, Matthieu Sarabi, Pascal Rihet, Véronique Baud, Nicolas F. Delahaye, Laetitia Peaudecerf, Isabelle Martins, Sylvie Bonvalot, Jan Tavernier, Eric Vivier, Nicolas Isambert, Michaela Semeraro, Isabelle Cremer, Marc Pallardy, Paule Opolon, Vichnou Poirier-Colame, Guido Kroemer, Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Chirurgie, Assistance Publique - Hôpitaux de Marseille (APHM)-Hospices Civiles de Marseille-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ), Department of Immunology, Duke University Medical Center, Institut Cochin (IC UM3 (UMR 8104 / U1016)), 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 - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), School of Medicine, Université Paris-Sud - Paris 11 (UP11), Recepteurs et Signalisation des Interleukines (U749), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de Pédiatrie, Institut Gustave Roussy (IGR), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Service d'anatomie pathologique [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Tenon [APHP], Département de biologie et pathologie médicales [Gustave Roussy], Vectorologie et transfert de gènes (VTG / UMR8121), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Università di Genova, Dipartimento di Medicina Sperimentale, Universita degli studi di Genova, Biochemistry, Ghent University [Belgium] (UGENT), 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), Département de pathologie, Institut Bergonié - CRLCC Bordeaux, Département de Médecine Nucléaire, Centre Léon Bérard [Lyon], Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Laboratory of Human Genetics of Infectious Diseases, Apoptose, cancer et immunité (U848), Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Pôle de biologie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Immunologie des tumeurs et immunothérapie ( UMR 1015 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Jacques Monod ( IJM ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Centre d'Investigation Clinique en Biotherapie des cancers ( CIC 1428 , CBT 507 ), Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance Publique - Hôpitaux de Marseille ( APHM ) -Hospices Civiles de Marseille-Hôpital de la Conception [CHU - APHM] ( LA CONCEPTION ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), 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 - Faculté de Médecine ( UPD5 Médecine ), Université Paris Descartes - Paris 5 ( UPD5 ), Université Paris-Sud - Paris 11 ( UP11 ), Recepteurs et Signalisation des Interleukines ( U749 ), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Gustave Roussy ( IGR ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Tenon [APHP], Vectorologie et transfert de gènes ( VTG / UMR8121 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Centre National de la Recherche Scientifique ( CNRS ), University of Genova, Ghent University [Belgium] ( UGENT ), Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques ( IP-TPT ), Institut de Recherche pour le Développement ( IRD ) -Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) -Service de Santé des Armées-Université de Montpellier ( UM ), Université Claude Bernard Lyon 1 ( UCBL ), Apoptose, cancer et immunité ( U848 ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), 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), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance Publique - Hôpitaux de Marseille (APHM)-Hospices Civiles de Marseille-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli studi di Genova = University of Genoa (UniGe), Universiteit Gent = Ghent University (UGENT), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Service de Santé des Armées, Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Universiteit Gent = Ghent University [Belgium] (UGENT)

Subjects
MESH: Interleukin-12, MESH : Alternative Splicing, MESH: Protein Isoforms, MESH: Lysosomal-Associated Membrane Protein 1, 0302 clinical medicine, Interferon, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Protein Isoforms, Receptor, MESH : Tumor Necrosis Factor-alpha, 0303 health sciences, MESH : Prognosis, MESH : Gastrointestinal Stromal Tumors, GiST, MESH : Lysosomal-Associated Membrane Protein 1, MESH: Alternative Splicing, MESH: Polymorphism, Single Nucleotide, MESH : Polymorphism, Single Nucleotide, General Medicine, Prognosis, Interleukin-12, MESH: Proto-Oncogene Proteins c-kit, Killer Cells, Natural, Proto-Oncogene Proteins c-kit, [SDV.IMM]Life Sciences [q-bio]/Immunology, Tumor necrosis factor alpha, MESH : Killer Cells, Natural, Sarcoma, MESH: Natural Cytotoxicity Triggering Receptor 3, Tyrosine kinase, MESH: Gastrointestinal Stromal Tumors, medicine.drug, MESH: Killer Cells, Natural, Gene isoform, MESH : Natural Cytotoxicity Triggering Receptor 3, MESH: Cell Line, Tumor, Stromal cell, MESH: Interferon-gamma, Gastrointestinal Stromal Tumors, Biology, Polymorphism, Single Nucleotide, MESH : Proto-Oncogene Proteins c-kit, MESH: Prognosis, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Interferon-gamma, Lysosomal-Associated Membrane Protein 1, Cell Line, Tumor, MESH : Interleukin-12, medicine, Humans, MESH : Interferon-gamma, 030304 developmental biology, MESH: Humans, Natural Cytotoxicity Triggering Receptor 3, MESH : Cell Line, Tumor, Tumor Necrosis Factor-alpha, MESH : Humans, MESH : Protein Isoforms, medicine.disease, Alternative Splicing, MESH: Tumor Necrosis Factor-alpha, Immunology, Cancer research, 030215 immunology
Abstract

International audience; The natural killer (NK) cell receptor NKp30 is involved in the recognition of tumor and dendritic cells (DCs). Here we describe the influence of three NKp30 splice variants on the prognosis of gastrointestinal sarcoma (GIST), a malignancy that expresses NKp30 ligands and that is treated with NK-stimulatory KIT tyrosine kinase inhibitors. Healthy individuals and those with GIST show distinct patterns of transcription of functionally different NKp30 isoforms. In a retrospective analysis of 80 individuals with GIST, predominant expression of the immunosuppressive NKp30c isoform (over the immunostimulatory NKp30a and NKp30b isoforms) was associated with reduced survival of subjects, decreased NKp30-dependent tumor necrosis factor-α (TNF-α) and CD107a release, and defective interferon-γ (IFN-γ) and interleukin-12 (IL-12) secretion in the NK-DC cross-talk that could be restored by blocking of IL-10. Preferential NKp30c expression resulted partly from a single-nucleotide polymorphism at position 3790 in the 3' untranslated region of the gene encoding NKp30. The genetically determined NKp30 status predicts the clinical outcomes of individuals with GIST independently from KIT mutation.

Published
2010

26. 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

27. 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

28. Tumor necrosis factor alpha and adalimumab differentially regulate CD36 expression in human monocytes

Author

Alain Cantagrel, José Bernad, Bernard Mazières, Jean Frédéric Boyer, Bernard Pipy, Hélène Authier, Jean-Luc Davignon, Arnaud Constantin, Patricia Balard, and Bruno Faucon

Subjects
CD36 Antigens, CD36, Immunology, Anti-Inflammatory Agents, Peroxisome proliferator-activated receptor, Gene Expression, Inflammation, Electrophoretic Mobility Shift Assay, Antibodies, Monoclonal, Humanized, Peripheral blood mononuclear cell, Monocytes, Arthritis, Rheumatoid, Immunoglobulin Fab Fragments, Rheumatology, Adalimumab, medicine, Immunology and Allergy, Humans, RNA, Messenger, Receptor, Cells, Cultured, chemistry.chemical_classification, NADPH oxidase, biology, Reverse Transcriptase Polymerase Chain Reaction, Tumor Necrosis Factor-alpha, Antibodies, Monoclonal, Atherosclerosis, Flow Cytometry, Molecular biology, PPAR gamma, chemistry, biology.protein, Cancer research, Tumor necrosis factor alpha, medicine.symptom, Reactive Oxygen Species, medicine.drug, Research Article
Abstract

In chronic inflammatory diseases, such as rheumatoid arthritis, inflammation acts as an independent cardiovascular risk factor and the use of anti-inflammatory drugs, such as anti-tumor necrosis factor alpha (anti-TNFalpha), may decrease this risk. The phagocytosis of oxidized low density lipoproteins (LDLs) accumulated in the subendothelium by mononuclear cells influences atherosclerosis and depends on CD36 expression. We investigated the role of TNFalpha and adalimumab, a human anti-TNFalpha monoclonal antibody widely used in human pathology, in CD36 expression in human monocytes. Human monocytes were prepared by adherence from whole-blood buffy-coat fractions from healthy donors. CD36 expression was assessed by RT-PCR and flow cytometry, with various TNFalpha or adalimumab concentrations. Implication of peroxisome proliferator-activated receptor (PPAR)gamma in the regulation of CD36 expression was assessed using specific inhibitor or gel shift assays. The impact of redox signaling was investigated using quantification of reactive oxygen species, antioxidant and a NADPH oxidase inhibitor. The F(ab')2 fragment of adalimumab was isolated and its effect was analyzed. TNFalpha inhibits both CD36 membrane expression and mRNA expression. This inhibition involves a reduction in PPARgamma activation. In contrast, adalimumab increases both CD36 membrane expression and mRNA expression. This induction is independent of the Fc portion of adalimumab and involves redox signaling via NADPH oxidase activation. CD36 expression on human monocytes is inhibited by TNFalpha and independently increased by adalimumab. These data highlight that pro-inflammatory cytokines and their specific neutralization influence the expression of cellular receptors implicated in atherosclerosis. Further studies are needed to investigate the clinical implications of these results in accelerated atherosclerosis observed in rheumatoid arthritis.

Published
2006

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