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

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

doi:10.1038/ncomms7801

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.

Highlights

Liver receptor homologue-1 (LRH-1) is a nuclear receptor involved in the repression of inflammatory processes in the hepatointestinal tract
We demonstrate that LRH-1 is induced by IL-13 via a STAT6dependent mechanism, which in turn induces the transcriptional activation of CYP1A1 and CYP1B1, two enzymes involved in the generation of 15-HETE PPARg ligand
On the basis of the current findings suggesting a role for LRH-1 in PPARg-mediated alternative polarization following IL-13 stimulation, we investigated whether deletion of LRH-1 in macrophages could have an impact on the outcome of Candida albicans infection

Summary

Introduction

Liver receptor homologue-1 (LRH-1) is a nuclear receptor involved in the repression of inflammatory processes in the hepatointestinal tract. Mice with LRH-1-deficient macrophages are, highly susceptible to gastrointestinal and systemic Candida albicans infection 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/PPARg axis. M1 macrophages express high levels of opsonic receptors, involved in the production of pro-inflammatory effector molecules such as reactive oxygen and nitrogen intermediates and proinflammatory cytokines (interleukin (IL)-1b, tumour-necrosis factor alpha (TNFa), IL-6 and IL-12) These macrophages contribute to inflammation, microbial killing, regulation of cell proliferation and apoptosis. In the colon from patients with inflammatory bowel disease, inflammation is inversely correlated with the expression of LRH-1 (refs 20,21) In line with these reports, Venteclef et al.[22,23] identified a role for LRH-1 in the negative modulation of the hepatic acute-phase response by inhibiting IL-6- and IL-1b-stimulated haptoglobin, serum amyloid A gene expression in hepatocytes and inducing antiinflammatory IL-1ra expression. We demonstrate the importance of intact LRH-1 signalling in the anti-inflammatory and antifungal functions of alternatively activated macrophages, indicating that modulators of LRH-1 activity may have therapeutic potential to restrain infectious and inflammatory diseases

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Conclusion