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Heme regulates the development of iron-recycling macrophages from monocytes (heme-treated BMM)

ABSTRACT: Splenic red pulp macrophages (RPM) degrade senescent erythrocytes and recycle heme-associated iron. The transcription factor Spic is selectively expressed by RPM and is required for their development, but the physiologic stimulus inducing Spic is unknown. Here, we report that Spic also regulated the development of F4/80+VCAM+ bone marrow macrophages (BMM) and that Spic expression in BMM and RPM development was induced by heme, a metabolite of erythrocyte degradation. Pathologic hemolysis induced loss of RPM and BMM due to excess heme but induced Spic in monocytes to generate new RPM and BMM. Spic expression in monocytes was constitutively inhibited by the transcriptional repressor Bach1. Heme induced proteasome-dependent BACH1 degradation and rapid Spic derepression. Further, cysteine-proline dipeptide motifs in BACH1 that mediate heme-dependent degradation were necessary for Spic induction by heme. These findings are the first example of metabolite-driven differentiation of a tissue-resident macrophage subset and provide new insight into iron homeostasis. Global gene expression pattern of bone marrow-derived macrophages generated with GM-CSF in vitro and treated with heme were compared to those treated with vehicle at 6 hours, 24 hours, and 72 hours after treatment.

ORGANISM(S): Mus musculus

PROVIDER: GSE46983 | GEO | 2014/03/14

SECONDARY ACCESSION(S): PRJNA203219

REPOSITORIES: GEO

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Heme regulates the development of iron-recycling macrophages from monocytes (heme-treated BMM)

Project description:Splenic red pulp macrophages (RPM) degrade senescent erythrocytes and recycle heme-associated iron. The transcription factor Spic is selectively expressed by RPM and is required for their development, but the physiologic stimulus inducing Spic is unknown. Here, we report that Spic also regulated the development of F4/80+VCAM+ bone marrow macrophages (BMM) and that Spic expression in BMM and RPM development was induced by heme, a metabolite of erythrocyte degradation. Pathologic hemolysis induced loss of RPM and BMM due to excess heme but induced Spic in monocytes to generate new RPM and BMM. Spic expression in monocytes was constitutively inhibited by the transcriptional repressor Bach1. Heme induced proteasome-dependent BACH1 degradation and rapid Spic derepression. Further, cysteine-proline dipeptide motifs in BACH1 that mediate heme-dependent degradation were necessary for Spic induction by heme. These findings are the first example of metabolite-driven differentiation of a tissue-resident macrophage subset and provide new insight into iron homeostasis. Global gene expression pattern of bone marrow-derived macrophages generated with GM-CSF in vitro and treated with heme were compared to those treated with vehicle at 6 hours, 24 hours, and 72 hours after treatment. GM-CSF cultures of Spic(igfp/igfp) BM cells were treated with heme (80 Âµm) or vehicle after 6 days in culture. Adherent fraction of cells were harvested 6 hours, 24 hours, and 72 hours after treatment and RNA was isolated using an RNeasy mini kit (Qiagen) and submitted for amplification, labeling and hybridization. Expression values were analyzed after RMA quantile normalization using ArrayStar software (DNASTAR).

2014-03-14 | E-GEOD-46983 | biostudies-arrayexpress

Heme-induced inhibition of Bach1derepresses Spic.

Project description:Splenic red pulp macrophages (RPM) degrade senescent erythrocytes and recycle heme-associated iron. The transcription factor Spic is selectively expressed by RPM and is required for their development, but the physiologic stimulus inducing Spic is unknown. Here, we report that Spic also regulated the development of F4/80+VCAM+ bone marrow macrophages (BMM) and that Spic expression in BMM and RPM development was induced by heme, a metabolite of erythrocyte degradation. Pathologic hemolysis induced loss of RPM and BMM due to excess heme but induced Spic in monocytes to generate new RPM and BMM. Spic expression in monocytes was constitutively inhibited by the transcriptional repressor Bach1. Heme induced proteasome-dependent BACH1 degradation and rapid Spic derepression. Further, cysteine-proline dipeptide motifs in BACH1 that mediate heme-dependent degradation were necessary for Spic induction by heme. These findings are the first example of metabolite-driven differentiation of a tissue-resident macrophage subset and provide new insight into iron homeostasis. Bone marrow derived macrophages were generated in vitro by culturing WT and Bach1 knock out bone marrow in the presence of GM-CSF and their global gene expression pattern were compared in the presence or absence of heme at the various indicated time points after treatment. GMP and MPP populations were sorted from fetal liver chimeras and pooled by donor genotype. RNA was isolated using an RNAqueous-Micro Kit (Ambion) and submitted for amplification, labeling and hybridization. Expression values were analyzed after RMA quantile normalization using ArrayStar software (DNASTAR).

2014-03-14 | E-GEOD-53796 | biostudies-arrayexpress

Heme-induced inhibition of Bach1derepresses Spic.

Project description:Splenic red pulp macrophages (RPM) degrade senescent erythrocytes and recycle heme-associated iron. The transcription factor Spic is selectively expressed by RPM and is required for their development, but the physiologic stimulus inducing Spic is unknown. Here, we report that Spic also regulated the development of F4/80+VCAM+ bone marrow macrophages (BMM) and that Spic expression in BMM and RPM development was induced by heme, a metabolite of erythrocyte degradation. Pathologic hemolysis induced loss of RPM and BMM due to excess heme but induced Spic in monocytes to generate new RPM and BMM. Spic expression in monocytes was constitutively inhibited by the transcriptional repressor Bach1. Heme induced proteasome-dependent BACH1 degradation and rapid Spic derepression. Further, cysteine-proline dipeptide motifs in BACH1 that mediate heme-dependent degradation were necessary for Spic induction by heme. These findings are the first example of metabolite-driven differentiation of a tissue-resident macrophage subset and provide new insight into iron homeostasis. Bone marrow derived macrophages were generated in vitro by culturing WT and Bach1 knock out bone marrow in the presence of GM-CSF and their global gene expression pattern were compared in the presence or absence of heme at the various indicated time points after treatment.

2014-03-14 | GSE53796 | GEO

Heme regulates the development of iron-recycling macrophages from monocytes (sorted splenocytes)

Project description:Splenic red pulp macrophages (RPM) degrade senescent erythrocytes and recycle heme-associated iron. The transcription factor Spic is selectively expressed by RPM and is required for their development, but the physiologic stimulus inducing Spic is unknown. Here, we report that Spic also regulated the development of F4/80+VCAM+ bone marrow macrophages (BMM) and that Spic expression in BMM and RPM development was induced by heme, a metabolite of erythrocyte degradation. Pathologic hemolysis induced loss of RPM and BMM due to excess heme but induced Spic in monocytes to generate new RPM and BMM. Spic expression in monocytes was constitutively inhibited by the transcriptional repressor Bach1. Heme induced proteasome-dependent BACH1 degradation and rapid Spic derepression. Further, cysteine-proline dipeptide motifs in BACH1 that mediate heme-dependent degradation were necessary for Spic induction by heme. These findings are the first example of metabolite-driven differentiation of a tissue-resident macrophage subset and provide new insight into iron homeostasis. Global gene expression pattern of Spic+ monocytes, Spic- monocytes, and Spic high red pulp macrophages were compared by sorting these cells from Spic(igfp/+) splenocytes and performing microarray-based gene expression profiling.

2014-03-14 | GSE46984 | GEO

Heme regulates the development of iron-recycling macrophages from monocytes (sorted splenocytes)

Project description:Splenic red pulp macrophages (RPM) degrade senescent erythrocytes and recycle heme-associated iron. The transcription factor Spic is selectively expressed by RPM and is required for their development, but the physiologic stimulus inducing Spic is unknown. Here, we report that Spic also regulated the development of F4/80+VCAM+ bone marrow macrophages (BMM) and that Spic expression in BMM and RPM development was induced by heme, a metabolite of erythrocyte degradation. Pathologic hemolysis induced loss of RPM and BMM due to excess heme but induced Spic in monocytes to generate new RPM and BMM. Spic expression in monocytes was constitutively inhibited by the transcriptional repressor Bach1. Heme induced proteasome-dependent BACH1 degradation and rapid Spic derepression. Further, cysteine-proline dipeptide motifs in BACH1 that mediate heme-dependent degradation were necessary for Spic induction by heme. These findings are the first example of metabolite-driven differentiation of a tissue-resident macrophage subset and provide new insight into iron homeostasis. Global gene expression pattern of Spic+ monocytes, Spic- monocytes, and Spic high red pulp macrophages were compared by sorting these cells from Spic(igfp/+) splenocytes and performing microarray-based gene expression profiling. Splenocytes were prepared from Spic(igfp/+) mice and were first negatively selected for CD4, CD8, and B220 by MACS (Miltenyi Biotech) purification using the respective microbeads. Negatively selected splenocytes were then stained with anti-CD11b and anti-Ly6c and sorted for Spic+ monocytes (CD11b+Ly6c+Spic+) and Spic- monocytes (CD11b+Ly6c+Spic-). Purified RPM were obtained by staining splenocytes with anti-F4/80 and sorting for F4/80 hi Spic-EGFP hi cells.

2014-03-14 | E-GEOD-46984 | biostudies-arrayexpress

Investigation of Bach1 function by heme-iron homeostasis in bone marrow derived macrophage

Project description:Macrophages are central in regulating iron homeostasis. Transcription repressor Bach1 regulates by heme. Here we investigated the relationship between heme-regulated Bach1 and bone marrow derived macrophage. We found that Bach1 KO macrophage showed that up-regulated genes were the process that iron-heme homeostasis and maintenance related gene compared with WT. Our results suggest that Bach1 expression is important to the heme homeostasis and maintenance in the bone marrow derived macrophage.

2019-03-30 | GSE79717 | GEO

Gene expression profile at single cell level of cells from subcutaneous implanted syngeneic fibrosarcoma tumors in C57BL/6 mice injected with autologous erythrocytes suspended in buffered saline

Project description:Iron-rich tumor-associated macrophages (iTAMs) are characterized by high intracellular iron, heme metabolism, and expression of the endothelin receptor B. iTAMs promote angiogenesis and immunosuppression in tumors. Heme-mediated degradation of the transcriptional repressor BACH1 induces the iTAM transcriptional program in macrophages.

2024-08-30 | GSE268581 | GEO

Gene expression profile at single cell level of iron positive and iron negative cells from subcutaneous implanted syngeneic fibrosarcoma tumors in C57BL/6 mice.

2024-08-30 | GSE269203 | GEO

Iron-Heme-Bach1 Axis Is Involved In Erythroblast Adaptation To Iron Deficiency

Project description:Iron plays the central role in the oxygen transport by the erythrocyte as a constituent of heme and hemoglobin. The importance of iron and heme also resides in their regulatory roles during erythroblast maturation. The transcription factor Bach1 may be involved in their regulatory roles since it is inactivated by direct binding of heme. To address whether Bach1 is involved in the responses of erythroblasts to iron status, low iron conditions that induced severe iron deficiency in mice were established. Under iron deficiency, extensive gene expression changes and mitophagy disorder were induced during maturation of erythroblasts. Bach1 mice showed more severe iron deficiency anemia in the developmental phase of mice and a retarded recovery once iron was replenished when compared with wild-type mice. In the absence of Bach1, the expression of globin genes and Hmox1 (encoding heme oxygenase-1) was de-repressed in erythroblasts under iron deficiency, suggesting that Bach1 represses these genes in erythroblasts under iron deficiency to balance the levels of heme and globin. Moreover, an increase in genome-wide DNA methylation was observed in erythroblasts of Bach1–/– mice under iron deficiency. These findings reveal the principle role of iron as a regulator of gene expression in erythroblast maturation and suggest that the iron-heme-Bach1 axis is important for a proper adaptation of erythroblast to iron deficiency to avoid toxic aggregates of non-heme globin.

2016-12-14 | GSE78955 | GEO

Genome-wide map of BACH1 binding in HEK 293T cells

Project description:BTB and CNC homology 1 (BACH1) is a heme-binding transcription factor repressing the transcription from a subset of MAF recognition elements (MAREs) at low intracellular heme levels. Upon heme binding, BACH1 is released from the MAREs, resulting in increased expression of antioxidant response genes. To systematically address the gene regulatory networks involving BACH1, we combined chromatin immunoprecipitation-sequencing (ChIP-seq) analysis of BACH1 target genes in HEK 293 cells with knock-down of BACH1 using three independent types of small interfering RNAs followed by transcriptome profiling using microarrays. The 59 BACH1 target genes identified by ChIP-seq were found highly enriched in genes showing expression changes after BACH1 knock-down, demonstrating the impact of BACH1 repression on transcription. In addition to known and new BACH1 targets involved in heme degradation (HMOX1, FTL, FTH1, ME1, SLC48A1) and redox regulation (GCLC, GCLM, SLC7A11), we also discovered BACH1 target genes effecting cell cycle and apoptosis pathways (ITPR2, CALM1, SQSTM1, TFE3, EWSR1, CDK6, BCL2L11, MAFG) as well as subcellular transport processes (CLSTN1, PSAP, MAPT, vault RNA). The newly identified impact of BACH1 on genes involved in neurodegenerative processes and proliferation provides an interesting basis for future dissection of BACH1-mediated gene repression in neurodegeneration and virus-induced cancerogenesis. Examination of BACH1 binding in HEK 293T cells by chromatin immunoprecipitation-sequencing (CHIP-seq) with input DNA as control.

2011-05-13 | E-GEOD-28051 | biostudies-arrayexpress

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