title: LRH-1 mediates anti-inflammatory and antifungal phenotype of IL-13-activated macrophages through the PPARγ ligand synthesis.
abstract: Liver receptor homologue-1 (LRH-1) is a nuclear receptor involved in the repression of inflammatory processes in the hepatointestinal tract. Here we report that LRH-1 is expressed in macrophages and induced by the Th2 cytokine IL-13 via a mechanism involving STAT6. We show that loss-of-function of LRH-1 in macrophages impedes IL-13-induced macrophage polarization due to impaired generation of 15-HETE PPARγ ligands. The incapacity to generate 15-HETE metabolites is at least partially caused by the compromised regulation of CYP1A1 and CYP1B1. Mice with LRH-1-deficient macrophages are, furthermore, highly susceptible to gastrointestinal and systemic Candida albicans infection. Altogether, these results identify LRH-1 as a critical component of the anti-inflammatory and fungicidal response of alternatively activated macrophages that acts upstream from the IL-13-induced 15-HETE/PPARγ axis.
authors: 1] UMR MD3, EA2405 Polarisation des Macrophages et Récepteurs Nucléaires dans les Pathologies Inflammatoires et Infectieuses, UPS, Toulouse 31400, France [2] Université de Toulouse, UMR 152, UPS, Toulouse 31400, France.
authors: Lise
authors: L
authors: Lefèvre
authors: 1] UMR MD3, EA2405 Polarisation des Macrophages et Récepteurs Nucléaires dans les Pathologies Inflammatoires et Infectieuses, UPS, Toulouse 31400, France [2] Université de Toulouse, UMR 152, UPS, Toulouse 31400, France.
authors: Hélène
authors: H
authors: Authier
authors: Metabolic Signaling, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne 1015, Switzerland.
authors: Sokrates
authors: S
authors: Stein
authors: Université de Toulouse, UMR 152, UPS, Toulouse 31400, France.
authors: Clarisse
authors: C
authors: Majorel
authors: EA4553 Individualisation des traitements des cancers ovariens et ORL, UPS, Toulouse 31400, France.
authors: Bettina
authors: B
authors: Couderc
authors: 1] UMR MD3, EA2405 Polarisation des Macrophages et Récepteurs Nucléaires dans les Pathologies Inflammatoires et Infectieuses, UPS, Toulouse 31400, France [2] Université de Toulouse, UMR 152, UPS, Toulouse 31400, France.
authors: Christophe
authors: C
authors: Dardenne
authors: Université de Toulouse, UMR 152, UPS, Toulouse 31400, France.
authors: Mohamad Ala
authors: MA
authors: Eddine
authors: 1] UMR MD3, EA2405 Polarisation des Macrophages et Récepteurs Nucléaires dans les Pathologies Inflammatoires et Infectieuses, UPS, Toulouse 31400, France [2] Université de Toulouse, UMR 152, UPS, Toulouse 31400, France.
authors: Etienne
authors: E
authors: Meunier
authors: 1] UMR MD3, EA2405 Polarisation des Macrophages et Récepteurs Nucléaires dans les Pathologies Inflammatoires et Infectieuses, UPS, Toulouse 31400, France [2] Université de Toulouse, UMR 152, UPS, Toulouse 31400, France.
authors: José
authors: J
authors: Bernad
authors: Université de Toulouse, UMR 152, UPS, Toulouse 31400, France.
authors: Alexis
authors: A
authors: Valentin
authors: 1] UMR MD3, EA2405 Polarisation des Macrophages et Récepteurs Nucléaires dans les Pathologies Inflammatoires et Infectieuses, UPS, Toulouse 31400, France [2] Université de Toulouse, UMR 152, UPS, Toulouse 31400, France.
authors: Bernard
authors: B
authors: Pipy
authors: Metabolic Signaling, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne 1015, Switzerland.
authors: Kristina
authors: K
authors: Schoonjans
authors: 1] UMR MD3, EA2405 Polarisation des Macrophages et Récepteurs Nucléaires dans les Pathologies Inflammatoires et Infectieuses, UPS, Toulouse 31400, France [2] Université de Toulouse, UMR 152, UPS, Toulouse 31400, France.
authors: Agnès
authors: A
authors: Coste
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002176:Candida albicans; D002177:Candidiasis / Q000276:immunology*; D047369:Chromatin Immunoprecipitation; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000276:immunology; D065633:Cytochrome P-450 CYP1B1 / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005759:Gastroenteritis / Q000276:immunology*; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000276:immunology; D018793:Interleukin-13 / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000276:immunology; D051379:Mice; D047495:PPAR gamma / Q000235:genetics* / Q000276:immunology; D010587:Phagocytosis / Q000235:genetics / Q000276:immunology; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050800:STAT6 Transcription Factor / Q000378:metabolism
chemical_list: D016207:Cytokines; D006893:Hydroxyeicosatetraenoic Acids; D018793:Interleukin-13; C082631:NR5A2 protein, human; C431936:Nr5a2 protein, mouse; D047495:PPAR gamma; D018160:Receptors, Cytoplasmic and Nuclear; D050800:STAT6 Transcription Factor; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; C585498:Cyp1b1 protein, mouse; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1