Mevalonate kinase (MK)-associated diseases encompass a broad spectrum of rare auto-inflammatory conditions, all resulting from pathogenic variants in the mevalonate kinase gene (MVK). Their clinical manifestations are...Mevalonate kinase (MK)-associated diseases encompass a broad spectrum of rare auto-inflammatory conditions, all resulting from pathogenic variants in the mevalonate kinase gene (MVK). Their clinical manifestations are highly variable, ranging from more or less serious systemic disorders, such as hereditary recurrent fevers, to purely localized pathologies such as porokeratosis. The oldest condition identified as linked to this gene is a metabolic disease called mevalonic aciduria, and the most recent is disseminated superficial actinic porokeratosis, a disease limited to the skin. The modes of inheritance of MK-associated diseases also diverge among the different subtypes: recessive for the systemic subtypes and dominant with a post-zygotic somatic genetic alteration for MVK-associated porokeratosis. This review quickly retraces the historical steps that led to the description of the various MK-associated disease phenotypes and to a better understanding of their pathophysiology, then summarizes and compares the different genetic mechanisms involved in this group of disorders, and finally discusses the diverse causes that could underlie this phenotypic heterogeneity.展开更多
Pregnane X receptor(PXR)is the major regulator of xenobiotic metabolism.PXR itself is controlled by various signaling molecules including glucocorticoids.Moreover,negative feed-back regulation has been proposed at the...Pregnane X receptor(PXR)is the major regulator of xenobiotic metabolism.PXR itself is controlled by various signaling molecules including glucocorticoids.Moreover,negative feed-back regulation has been proposed at the transcriptional level.We examined the involvement of the 3’-untranslated region(3’-UTR)of NR1I2 mRNA and microRNAs in PXR-and glucocorticoid receptor(GR)-mediated regulation of NR1I2 gene expression.PXR ligands were found to significantly downregulate NR1I2 mRNA expression in a set of 14 human hepatocyte cultures.Similarly,PXR was downregulated by PCN in the C57/BL6 mice liver.In mechanistic studies with the full-length 3’-UTR cloned into luciferase reporter or expression vectors,we showed that the 3’-UTR reduces PXR expression.From the miRNAs tested,miR-18a-5p inhibited both NR 112 expression and CYP3A4 gene induction.Importantly,we observed significant upregulation of miR-18a-5p expression 6 h after treatment with the PXR ligand rifampicin,which indicates a putative mechanism underlying NR1I2 negative feed-back regulation in hepatic cells.Additionally,glucocorticoids upregulated NR1I2 expression not only through the promoter region but also via 3’-UTR regulation,which likely involves downregulation of miR-18a-5p.We conclude that miR-18a-5p is involved in the down-regulation of NR1I2expression by its ligands and in the upregulation of NR1I2 mRNA expression by glucocorticoids in hepatic cells.展开更多
Mesenchymal stromal cells(MSCs)possess well-described immunoregulatory properties,yet their capacity to drive regeneration in vertebrates is still debated and their mechanisms of action remain to be fully elucidated.I...Mesenchymal stromal cells(MSCs)possess well-described immunoregulatory properties,yet their capacity to drive regeneration in vertebrates is still debated and their mechanisms of action remain to be fully elucidated.In this study,we used zebrafish larvae,a highly regenerative vertebrate model to study the effects of MSC delivery on caudal fin fold regeneration and monitored macrophage dynamics through live imaging in fluorescent reporter lines.We found that MSCs enhanced fin regeneration by increasing the early recruitment of inflammatory(tnfa+)macrophages at 1-day-post-amputation(dpA),and accelerating resolution between 2 and 3 dpA.Given the established role of prostaglandin E2(PGE2)in MSC-mediated immunoregulation,we examined its contribution using indomethacin,a cyclooxygenase inhibitor that suppresses PGE2 production in grafted MSCs.We observed that PGE2 inhibition abolished the pro-regenerative effect of MSCs and maintained elevated tnfa+macrophage levels.PGE2-inhibited MSCs were more susceptible to phagocytosis by both zebrafish and mammalian macrophages,while maintaining viability,indicating a loss of PGE2-mediated protection in treated cells.Together,these findings demonstrate that MSC-derived PGE2 is essential for MSC regenerative function by promoting MSC persistence and modulating macrophage behavior,highlight the zebrafish as a powerful in vivo platform to dissect stem cell–immune interactions and optimize MSC-based regenerative strategies.展开更多
文摘Mevalonate kinase (MK)-associated diseases encompass a broad spectrum of rare auto-inflammatory conditions, all resulting from pathogenic variants in the mevalonate kinase gene (MVK). Their clinical manifestations are highly variable, ranging from more or less serious systemic disorders, such as hereditary recurrent fevers, to purely localized pathologies such as porokeratosis. The oldest condition identified as linked to this gene is a metabolic disease called mevalonic aciduria, and the most recent is disseminated superficial actinic porokeratosis, a disease limited to the skin. The modes of inheritance of MK-associated diseases also diverge among the different subtypes: recessive for the systemic subtypes and dominant with a post-zygotic somatic genetic alteration for MVK-associated porokeratosis. This review quickly retraces the historical steps that led to the description of the various MK-associated disease phenotypes and to a better understanding of their pathophysiology, then summarizes and compares the different genetic mechanisms involved in this group of disorders, and finally discusses the diverse causes that could underlie this phenotypic heterogeneity.
基金supported by grants from the Czech Science Foundation 17-06841S to Petr PavekEFSA-CDN(No.CZ.02.1.01/0.0/0.0/16_019/0000841,Czech Republic)co-funded by ERDF to Tomas Smutny.
文摘Pregnane X receptor(PXR)is the major regulator of xenobiotic metabolism.PXR itself is controlled by various signaling molecules including glucocorticoids.Moreover,negative feed-back regulation has been proposed at the transcriptional level.We examined the involvement of the 3’-untranslated region(3’-UTR)of NR1I2 mRNA and microRNAs in PXR-and glucocorticoid receptor(GR)-mediated regulation of NR1I2 gene expression.PXR ligands were found to significantly downregulate NR1I2 mRNA expression in a set of 14 human hepatocyte cultures.Similarly,PXR was downregulated by PCN in the C57/BL6 mice liver.In mechanistic studies with the full-length 3’-UTR cloned into luciferase reporter or expression vectors,we showed that the 3’-UTR reduces PXR expression.From the miRNAs tested,miR-18a-5p inhibited both NR 112 expression and CYP3A4 gene induction.Importantly,we observed significant upregulation of miR-18a-5p expression 6 h after treatment with the PXR ligand rifampicin,which indicates a putative mechanism underlying NR1I2 negative feed-back regulation in hepatic cells.Additionally,glucocorticoids upregulated NR1I2 expression not only through the promoter region but also via 3’-UTR regulation,which likely involves downregulation of miR-18a-5p.We conclude that miR-18a-5p is involved in the down-regulation of NR1I2expression by its ligands and in the upregulation of NR1I2 mRNA expression by glucocorticoids in hepatic cells.
基金funded by University of Montpellier,Inserm and by research grants from the French National Research Agency(ANR)for the“PPAROA”project(ANR-18-CE18-0010–01)“METABOA”project(ANR-20-CE18-0014)“PEPR iCHONDRO”project(ANR-22-PEBI-0002).
文摘Mesenchymal stromal cells(MSCs)possess well-described immunoregulatory properties,yet their capacity to drive regeneration in vertebrates is still debated and their mechanisms of action remain to be fully elucidated.In this study,we used zebrafish larvae,a highly regenerative vertebrate model to study the effects of MSC delivery on caudal fin fold regeneration and monitored macrophage dynamics through live imaging in fluorescent reporter lines.We found that MSCs enhanced fin regeneration by increasing the early recruitment of inflammatory(tnfa+)macrophages at 1-day-post-amputation(dpA),and accelerating resolution between 2 and 3 dpA.Given the established role of prostaglandin E2(PGE2)in MSC-mediated immunoregulation,we examined its contribution using indomethacin,a cyclooxygenase inhibitor that suppresses PGE2 production in grafted MSCs.We observed that PGE2 inhibition abolished the pro-regenerative effect of MSCs and maintained elevated tnfa+macrophage levels.PGE2-inhibited MSCs were more susceptible to phagocytosis by both zebrafish and mammalian macrophages,while maintaining viability,indicating a loss of PGE2-mediated protection in treated cells.Together,these findings demonstrate that MSC-derived PGE2 is essential for MSC regenerative function by promoting MSC persistence and modulating macrophage behavior,highlight the zebrafish as a powerful in vivo platform to dissect stem cell–immune interactions and optimize MSC-based regenerative strategies.
