Dendritic cell-derived hepcidin sequesters iron from the microbiota to promote mucosal healing
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ABSTRACT:
PROVIDER: PRJNA579388 | ENA |
REPOSITORIES: ENA
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Project description:Bleeding and altered iron distribution occur in multiple gastrointestinal diseases, but the significance or regulation of these changes remains unclear. Here we report that hepcidin, the master regulator of systemic iron homeostasis, is required for tissue repair in the intestine following experimental damage. This effect was independent of hepatocyte-derived hepcidin or systemic iron levels. Rather, we identified that conventional dendritic cells (DCs) are a source of hepcidin that is induced by microbial stimulation, prominent in the inflamed intestine of humans, and essential for tissue repair. Mechanistically, DC-derived hepcidin acted on ferroportin-expressing phagocytes to promote local iron sequestration, which regulated the microbiota and subsequently facilitated intestinal repair. Collectively, these results identify a novel pathway whereby DC-derived hepcidin promotes mucosal healing in the intestine via nutritional immunity.
2020-04-15 | GSE139371 | GEO
Project description: Not available
| S-EPMC7724573 | biostudies-literature
Project description:Iron-related disorders are among the most prevalent diseases worldwide. Systemic iron homeostasis requires hepcidin (Hamp), a hepatic-derived hormone that controls iron mobilization through its molecular target, ferroportin (FPN), the only known mammalian iron exporter. Here, we took a transcriptomic approach to to compare the duodenal transcriptome during systemic iron demand to that of hepcidin-deficiency iron overload. Hampfl/fl (control) and AlbCreERT2;Hampfl/fl mice were placed on iron-replete and low-iron diets and were sacrificed two weeks following tamoxifen treatment. Duodenum RNA expression was compared across genotypes and across iron-replete and low iron diets.
2018-12-12 | E-MTAB-7329 | biostudies-arrayexpress
Project description:Liver iron overload can induce hepatic expression of hepcidin and regulates iron metabolism. However, the mechanism of iron regulating iron metabolism remains known. Intracellular labile iron represents the nonferritin-bound, redox-active iron which is transitory and serves as a crossroad of cell iron metabolism. The role of intracellular labile iron played in iron metabolism has largely been elucidated. Here we show that intracellular labile iron of hepatocytes has dual function in iron metabolism. It can induce hepatocytes expressing hepcidin via ER stress induced transcription factors on the one hand, on the other hand stimulate BMP2 and BMP6 expression of liver sinusoidal endothelial cells (LSECs) though TNFα secreted by hepatocytes to further regulate iron metabolism. Blockade of TNFα could dysregulate the iron metabolism during iron overload. Our findings reveal the important role of intracellular labile iron in iron metabolism and represent a novel way to modulate iron metabolism during iron overload.
2023-05-03 | GSE186655 | GEO
Project description:Iron induces hepcidin by activating bone morphogenetic protein (BMP)6-SMAD signaling, which is critical for regulation of systemic iron homeostasis. High iron levels induce BMP6 production in liver endothelial cells, but the molecular mechanisms by which iron regulates BMP6 are incompletely understood. To address this, we performed RNA-sequencing on sorted liver endothelial cells from iron-adequate and iron-loaded mice.
2023-12-25 | GSE223871 | GEO
Project description:Background & Aims: Although hepcidin expression was shown to be induced by the BMP signaling pathway, it is not yet known how iron regulates hepcidin and which of the BMP molecules is the endogenous regulator of iron homeostasis in vivo. We therefore assessed liver transcription profiles of mice fed an iron-deficient or an iron-enriched diet and looked for genes that were regulated similarly to hepcidin in that context. Methods: Genome-wide liver expression profiles of mice of the B6 and D2 genetic backgrounds subjected to iron-deficient, -balanced, or -enriched diets were obtained using Agilent Whole Genome microarrays. Real-time quantitative-PCR and western-blots were used to confirm microarray results and compare gene expression variations induced by secondary iron deficiency or iron overload with those consecutive to Smad4 or Hamp1-deficiency. Results: Among 1419 transcripts significantly modulated by the dietary iron content, four were regulated similarly to the hepcidin genes Hamp1 and Hamp2. They are coding for Bmp6, the regulator of Bmp/Smad signal transduction Smad7, the negative regulator of basic helix-loop-helix (bHLH) proteins Id1, and a protein with a bHLH domain, Atoh8. The iron overload developed by Smad4 and Hamp1-deficient mice also increased Bmp6 transcription. Body iron stores influence Smad1/5/8 phosphorylation and, as shown by analysis of mice with liver-specific disruption of Smad4, the binding partner for the receptor-activated Smads is necessary for activation of Smad7, Id1, and Atoh8 transcription by iron. Conclusions: Liver expression of Bmp6, Smad7, Id1, and Atoh8 is regulated by body iron stores and may participate in hepcidin regulation through the Bmp/Smad pathway. Keywords: response to dietary iron content
2008-07-07 | GSE10421 | GEO
Project description:Iron is an essential trace element whose absorption is usually tightly regulated in the duodenum. HFE-related hereditary hemochromatosis (HH) is characterized by abnormally low expression of the iron-regulatory hormone, hepcidin, which results in increased iron absorption. The liver is crucial for iron homeostasis as it is the main production site of hepcidin. The aim of this study was to explore and compare the genome-wide transcriptome response to Hfe deficiency and dietary iron overload in murine liver and duodenum.
2009-09-05 | GSE17969 | GEO
Project description:Here we report the beneficial effects of a newly identified dermal cell subpopulation expressing the ATP-binding cassette subfamily B member 5 (ABCB5) for the therapy of non-healing wounds. Local administration of dermal ABCB5+-derived MSCs attenuated macrophage-dominated inflammation and thereby accelerated healing of full-thickness excisional wounds in the iron overload mouse model mimicking the non-healing state of human venous leg ulcers. The observed beneficial effects were due to interleukin-1 receptor antagonist (IL-1RA) secreted by ABCB5+-derived MSCs, which dampened inflammation and shifted the prevalence of unrestrained pro-inflammatory M1 macrophages towards repair promoting anti-inflammatory M2 macrophages at the wound site. The beneficial anti-inflammatory effect of IL-1RA released from ABCB5+-derived MSCs on human wound macrophages was conserved in humanized NOD-scid IL2rγnull mice. In conclusion, human dermal ABCB5+ cells represent a novel, easy accessible and marker-enriched source of MSCs which holds substantial promise to successfully treat chronic non-healing wounds in humans.
2019-01-30 | GSE125829 | GEO
Project description:miR-Seq on paired skin and oral mucosal wound healing
| PRJNA501906 | ENA
Project description:The activity of the potent nasal adjuvant flagellin depends on initial activation of airway epithelilal cells. This study aims at investigating the immune cells involved in the antigen presentation within the respiratory tract. First, microarrays characterized that activation/recruitment of immune cells was the main signature of flagellin activation in lung. Neutrophils and classical monocytes were strongly recruited into the lungs and take up antigen upon nasal administration of flagellin. In contrast, the numbers of lung CD11b+ or CD103+ DC and alveolar macrophages were not enhanced although these cells were very efficient in antigen uptake. Our experiments showed that CD11b+ DC but not monocytes, PMN, CD103+ DC are not essential for the adjuvant effect. Flagellin signaling enhanced the functional activation of lung CD11b+ conventional DC and their migration to the lymph nodes. Using Cd11c-DTR mice, CD11b+ DC from lymph nodes were identified as the major stimulators of CD4 T cell activation. Finally, the migration and maturation of mucosal DC was independent of direct signaling, highlighting the contribution of epithelial factors in the mucosal adjuvant effect of flagellin. In conclusion, these data demonstrate that adjuvant activity can be dissociated from inflammatory cell recruitment an open new perpectives for improvement of vaccines. Female C57BL/6J (6 weeks old) mice were immunized with the TLR5 agonist Flagellin (1μg diluted in PBS) by intranasal (i.n.) administration. Blood samples of four time points post immunization were taken at 2h, 4h, 18h and 48h. Microarray experiments were performed as single-color hybridizations.
2014-01-01 | E-GEOD-46421 | biostudies-arrayexpress