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
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blotting, Western
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Candida albicans
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Candidiasis / immunology*
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Chromatin Immunoprecipitation
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Cytochrome P-450 CYP1A1 / genetics
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Cytochrome P-450 CYP1A1 / immunology
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Cytochrome P-450 CYP1B1 / genetics
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Cytochrome P-450 CYP1B1 / immunology
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Cytokines / immunology
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Enzyme-Linked Immunosorbent Assay
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Flow Cytometry
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Gastroenteritis / immunology*
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Humans
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Hydroxyeicosatetraenoic Acids / immunology
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Interleukin-13 / immunology*
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Macrophages / immunology*
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Macrophages, Peritoneal / immunology
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Mice
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PPAR gamma / genetics*
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PPAR gamma / immunology
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Phagocytosis / genetics
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Phagocytosis / immunology
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Phenotype
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Real-Time Polymerase Chain Reaction
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Receptors, Cytoplasmic and Nuclear / genetics*
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Receptors, Cytoplasmic and Nuclear / immunology
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Reverse Transcriptase Polymerase Chain Reaction
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STAT6 Transcription Factor / metabolism
Substances
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Cytokines
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Hydroxyeicosatetraenoic Acids
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Interleukin-13
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NR5A2 protein, human
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Nr5a2 protein, mouse
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PPAR gamma
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Receptors, Cytoplasmic and Nuclear
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STAT6 Transcription Factor
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15-hydroxy-5,8,11,13-eicosatetraenoic acid
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Cyp1b1 protein, mouse
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Cytochrome P-450 CYP1A1
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Cytochrome P-450 CYP1B1