Heme-mediated SPI-C induction promotes monocyte differentiation into iron-recycling macrophages
Open accessAbstract
Splenic red pulp macrophages (RPM) degrade senescent erythrocytes and recycle heme-associated iron. The transcription factor SPI-C 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(+)VCAM1(+) 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. Furthermore, 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 insights into iron homeostasis.
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SpiC reprograms monocytes to acquire an iron-recycling macrophage phenotype.
“SpiC then reprograms monocytes to acquire an iron-recycling macrophage phenotype (Haldar et al., 2014).”
From Iron in infection and immunity (2020) · cites this paper as Haldar et al., 2014
Heme promotes monocyte differentiation into iron-recycling macrophages by inducing the master transcription factor for macrophage differentiation SPI-C, through direct inhibition of its repressor BACH1.
“Interestingly, heme promotes monocyte differentiation into iron-recycling macrophages by inducing the master transcription factor for macrophage differentiation SPI-C, through direction inhibition of its repressor BACH1 (Haldar et al., 2014).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Haldar et al., 2014
SpiC and its down-stream effector Hmox1 are both essential for EIM differentiation, since ablation of either gene reduces EIM number.
“The transcription factor SpiC and its down-stream effector Hmox1 are both essential for EIM differentiation, since ablation of either gene reduces EIM number [73, 88].”
From “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels (2017) · cites this paper as [88]
RPM and KC express the complete machinery for RBC clearance and heme iron recycling.
“It is well established that RPM and KC express the complete machinery for RBC clearance and heme iron recycling [72, 88, 231].”
From “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels (2017) · cites this paper as [88]
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- Authors
- Haldar, M., Kohyama, M., So, A. Y.-L., KC, W., Wu, X., Briseño, C. G., Satpathy, A. T., Kretzer, N. M., Arase, H., Rajasekaran, N. S., Wang, L., Egawa, T., Igarashi, K., Baltimore, D., Murphy, T. L., & Murphy, K. M.
- Affiliations
- Washington University in St. Louis (US)
- Immunology Frontier Research Center, The University of Osaka (JP)
- California Institute of Technology (US)
- University of Utah (US)
- Tohoku University (JP)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Murphy, Kenneth M.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-03
- Volume
- 156
- Issue
- 6
- Pages
- 1223-1234
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4010949
- OpenAlex
- W2087101282
- Cited by
- 431
- References
- 48
- Citations by year
- 2026: 37 · 2025: 30 · 2024: 31 · 2023: 29 · 2022: 34 · 2021: 40 · 2020: 47 · 2019: 38 · 2018: 34 · 2017: 32 · 2016: 33 · 2015: 34 · 2014: 11
- FWCI
- 26.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Japan Society for the Promotion of Science (24659223, 25670143)
- National Heart, Lung, and Blood Institute (K99HL118754)
- National Cancer Institute (T32 CA 9547-27, T32CA009547)
- National Institute of Allergy and Infectious Diseases (AI076427-02, R01AI076427, R01AI097244, R01AI093531, K08AI106953, T32AI007163)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
- Keywords
- heme, bone marrow-derived macrophages, monocyte differentiation, iron recycling, BACH1, proteasomal degradation, hemolysis, iron homeostasis, transcriptional repressor
- MeSH terms
- Animals, Bone Marrow Cells, Cell Differentiation, DNA-Binding Proteins, Female, Heme, Iron, Macrophages, Male, Mice, Inbred C57BL, Monocytes, Spleen, Myeloid Cells, Basic-Leucine Zipper Transcription Factors, Mice, Mice, 129 Strain
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