LRH-1 mediates anti-inflammatory and antifungal phenotype of IL-13-activated macrophages through the PPARγ ligand synthesis

Lise Lefèvre; Hélène Authier; Sokrates Stein; Clarisse Majorel; Bettina Couderc; Christophe Dardenne; Mohamad Ala Eddine; Etienne Meunier; José Bernad; Alexis Valentin; Bernard Pipy; Kristina Schoonjans; Agnès Coste

doi:10.1038/ncomms7801

LRH-1 mediates anti-inflammatory and antifungal phenotype of IL-13-activated macrophages through the PPARγ ligand synthesis

Nat Commun. 2015 Apr 15:6:6801. doi: 10.1038/ncomms7801.

Affiliations

¹ 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.
² Metabolic Signaling, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne 1015, Switzerland.
³ Université de Toulouse, UMR 152, UPS, Toulouse 31400, France.
⁴ EA4553 Individualisation des traitements des cancers ovariens et ORL, UPS, Toulouse 31400, France.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blotting, Western
Candida albicans
Candidiasis / immunology*
Chromatin Immunoprecipitation
Cytochrome P-450 CYP1A1 / genetics
Cytochrome P-450 CYP1A1 / immunology
Cytochrome P-450 CYP1B1 / genetics
Cytochrome P-450 CYP1B1 / immunology
Cytokines / immunology
Enzyme-Linked Immunosorbent Assay
Flow Cytometry
Gastroenteritis / immunology*
Humans
Hydroxyeicosatetraenoic Acids / immunology
Interleukin-13 / immunology*
Macrophages / immunology*
Macrophages, Peritoneal / immunology
Mice
PPAR gamma / genetics*
PPAR gamma / immunology
Phagocytosis / genetics
Phagocytosis / immunology
Phenotype
Real-Time Polymerase Chain Reaction
Receptors, Cytoplasmic and Nuclear / genetics*
Receptors, Cytoplasmic and Nuclear / immunology
Reverse Transcriptase Polymerase Chain Reaction
STAT6 Transcription Factor / metabolism

Substances

Cytokines
Hydroxyeicosatetraenoic Acids
Interleukin-13
NR5A2 protein, human
Nr5a2 protein, mouse
PPAR gamma
Receptors, Cytoplasmic and Nuclear
STAT6 Transcription Factor
15-hydroxy-5,8,11,13-eicosatetraenoic acid
Cyp1b1 protein, mouse
Cytochrome P-450 CYP1A1
Cytochrome P-450 CYP1B1