Hrg1 promotes heme-iron recycling during erythrophagocytosis in zebrafish kidne
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA432507 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6661140.fastq.gz | Fastqsanger.gz | |||
| SRR6661150.fastq.gz | Fastqsanger.gz | |||
| SRR6661141.fastq.gz | Fastqsanger.gz | |||
| SRR6661151.fastq.gz | Fastqsanger.gz | |||
| SRR6661142.fastq.gz | Fastqsanger.gz |
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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.
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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.
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Project description:Aging affects iron homeostasis and erythropoiesis, as evidenced by tissue iron loading in rodents and common anemia in the elderly. Given thatred pulp macrophages (RPMs) continuously process iron, their cellular functions might be susceptible to age-dependent decline, affecting organismal iron metabolism and red blood cell (RBCs) parameters. However, little is known about the effects of aging on the functioning of RPMs. To study aging RPMs, we employed 10-11-months-old female mice that show serum iron deficiency and iron overload primarily in spleens compared to young controls. We observed that this is associated with iron loading, oxidative stress, diminished lysosomal activity, and decreased erythrophagocytosis rate in RPMs. We uncovered that these impairments of RPMs lead to the retention of senescent RBCs in the spleen, their excessive local hemolysis, and the formation of iron- and heme-rich large extracellular protein aggregates, likely derived from damaged ferroptotic RPMs. We further found that feeding mice an iron-reduced diet alleviates iron accumulation and reactive oxygen species build-up in RPMs, improves their ability to clear and degrade erythrocytes, and limits ferroptosis. Consequently, this diet improves splenic RBCs fitness, limits hemolysis and the formation of iron-rich protein aggregates, and increases serum iron availability in aging mice. Using RPM-like cells, we show that diminished erythrophagocytic and lysosomal activities of RPMs can be attributed to a combination of increased iron levels and reduced expression of heme-catabolizing enzyme heme oxygenase 1 (HO-1). Taken together, we identified RPM dysfunction as an early hallmark of physiological aging and demonstrated that dietary iron reduction improves iron turnover efficacy.
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