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

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

doi:10.1038/ncomms7801

Cited by 50 publications

(66 citation statements)

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“…Of interest, LRH-1 expression was not completely absent, suggesting that the remaining LRH-1 expression is derived from a different cellular source, e.g. as previously shown by us for T cells [32] and others for macrophages [33]. While the inଏammation-driven induction of the steroidogenic enzymes Cyp11b1, Cyp11a1 and Cyp21 was evident in control animals, epithelial-speciଏc deletion of LRH-1 resulted in a signiଏcant reduction of the expression of these enzymes ( Fig.…”

Section: Lrh-1-dependent Expression Of Steroidogenic Enzymes In the Csupporting

confidence: 51%

Intestinal glucocorticoid synthesis enzymes in pediatric inflammatory bowel disease patients

et al. 2019

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Inଏammatory bowel disease (IBD), such as Crohn's disease and ulcerative colitis are devastating chronic immunopathologies of the intestinal mucosa, which are frequently treated by immunosuppressive glucocorticoids. Endogenous glucocorticoids are not only produced by the adrenal glands, but also by the intestinal epithelium. Local glucocorticoid synthesis critically contributes to the immune homeostasis of the intestinal mucosa. As defective intestinal glucocorticoid synthesis has been associated with the development of IBD, we investigated the expression of steroidogenic enzymes and the key transcriptional regulator Liver Receptor Homolog-1 (LRH-1/NR5A2) in ileal and colonic biopsies human pediatric IBD and control patients. Furthermore, the induction of steroidogenic enzymes and their transcriptional regulation by LRH-1 was investigated in a mouse model of experimental colitis. These analyses revealed that colitis-induced expression of steroidogenic enzymes in the murine colon is dependent on the presence of LRH-1, as intestinal deletion of LRH-1 strongly reduced their colitis-induced expression. Similarly, a strong correlation between the expression of LRH-1 and different steroidogenic enzymes was seen in intestinal biopsies of human pediatric patients. Importantly, reduced expression of hydroxysteroid dehydrogenase 11B1 (HSD11B1) was observed in IBD patients compared to control patients, suggesting that defective local reactivation of glucocorticoids could contribute to the pathogenesis of IBD.

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Section: Lrh-1-dependent Expression Of Steroidogenic Enzymes In the Csupporting

confidence: 51%

Intestinal glucocorticoid synthesis enzymes in pediatric inflammatory bowel disease patients

et al. 2019

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“…4E). PPAR␥ is a key transcription factor necessary for M2 differentiation, and its expression is induced by IL4, likely in a STAT6 dependent manner (17)(18)(19). We hypothesized that promoter histone arginine methylation can regulate PPAR␥ expres- sion in IL4-differentiated cells.…”

Section: Monocyte To Macrophage Differentiation Induces Prmt1 Expressmentioning

confidence: 99%

Protein arginine methyltransferase 1 modulates innate immune responses through regulation of peroxisome proliferator-activated receptor γ-dependent macrophage differentiation

Tikhanovich

Zhao

Olson

et al. 2017

Journal of Biological Chemistry

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Arginine methylation is a common posttranslational modification that has been shown to regulate both gene expression and extranuclear signaling events. We recently reported defects in protein arginine methyltransferase 1 (PRMT1) activity and arginine methylation in the livers of cirrhosis patients with a history of recurrent infections. To examine the role of PRMT1 in innate immune responses , we created a cell type-specific knock-out mouse model. We showed that myeloid-specific PRMT1 knock-out mice demonstrate higher proinflammatory cytokine production and a lower survival rate after cecal ligation and puncture. We found that this defect is because of defective peroxisome proliferator-activated receptor γ (PPARγ)-dependent M2 macrophage differentiation. PPARγ is one of the key transcription factors regulating macrophage polarization toward a more anti-inflammatory and pro-resolving phenotype. We found that PRMT1 knock-out macrophages failed to up-regulate PPARγ expression in response to IL4 treatment resulting in 4-fold lower PPARγ expression in knock-out cells than in wild-type cells. Detailed study of the mechanism revealed that PRMT1 regulates PPARγ gene expression through histone H4R3me2a methylation at the PPARγ promoter. Supplementing with PPARγ agonists rosiglitazone and GW1929 was sufficient to restore M2 differentiation and and abrogated the difference in survival between wild-type and PRMT1 knock-out mice. Taken together these data suggest that PRMT1-dependent regulation of macrophage PPARγ expression contributes to the infection susceptibility in PRMT1 knock-out mice.

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“…Finally, cytochrome P450 enzymes (e.g. CYP1A1 and CYP1B1) represent another pathway that metabolizes AA or AA-derived mediators, thus further enhancing the immunoregulatory repertoire of eicosanoids (Nebert and Karp, 2008;Divanovic et al, 2013;Lefèvre et al, 2015). Indeed, there is a large body of literature describing the regulation and immunological functions of eicosanoids and not all studies could be covered in this review.…”

Section: Introductionmentioning

confidence: 99%

Immune-regulation and -functions of eicosanoid lipid mediators

Bieren¹

2017

Biological Chemistry

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Bioactive lipids regulate most physiological processes, from digestion to blood flow and from hemostasis to labor. Lipid mediators are also involved in multiple pathologies including cancer, autoimmunity or asthma. The pathological roles of lipid mediators are based on their intricate involvement in the immune system, which comprises source and target cells of these mediators. Based on their biosynthetic origin, bioactive lipids can be grouped into different classes [e.g. sphingolipids, formed from sphingosine or eicosanoids, formed from arachidonic acid (AA)]. Owing to the complexity of different mediator classes and the prominent immunological roles of eicosanoids, this review will focus solely on the immune-regulation of eicosanoids. Eicosanoids do not only control key immune responses (e.g. chemotaxis, antigen presentation, phagocytosis), but they are also subject to reciprocal control by the immune system. Particularly, key immunoregulatory cytokines such as IL-4 and IFN-γ shape the cellular eicosanoid profile, thus providing efficient feedback regulation between cytokine and eicosanoid networks. For the purpose of this review, I will first provide a short overview of the most important immunological functions of eicosanoids with a focus on prostaglandins (PGs) and leukotrienes (LTs). Second, I will summarize the current knowledge on immunological factors that regulate eicosanoid production during infection and inflammation.

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

Cited by 50 publications

References 50 publications

Intestinal glucocorticoid synthesis enzymes in pediatric inflammatory bowel disease patients

Intestinal glucocorticoid synthesis enzymes in pediatric inflammatory bowel disease patients

Protein arginine methyltransferase 1 modulates innate immune responses through regulation of peroxisome proliferator-activated receptor γ-dependent macrophage differentiation

Immune-regulation and -functions of eicosanoid lipid mediators

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