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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 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
In the citing paper
“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
In the citing paper
“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]
In the citing paper
“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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BackgroundCD169-CD43 interaction is involved in erythroblastic island formation and erythroid differentiation
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BackgroundInfluentialRenal control of life-threatening malarial anemia
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“Mechanistically, Spic is derepressed by heme, leading to differentiation of splenic RPM and bone marrow macrophages ( 8 , 9 ).”
InfluentialPradhan, P., Vijayan, V., Liu, B., Martínez–Delgado, B., Matamala, N., Nikolin, C., Greite, R., DeLuca, D. S., Janciauskiene, S. M., Motterlini, R., et al. (2024) · Redox Biology · doi:10.1016/j.redox.2024.103191 · Cited by 20
“Moreover, heme is a crucial signaling molecule and is involved in differentiation of tissue-specific iron-recycling macrophages [4,5].”
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MiR-155 enhances phagocytic activity of β-thalassemia/HbE monocytes via targeting of BACH1
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“BACH-1 gets activated during the development of monocyte to macrophage in spleen and bone marrow [29].”
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Identification of a Negative Regulatory Role for Spi-C in the Murine B Cell Lineage
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Tissue‐resident macrophages — how to humanize our knowledge
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“Transcription factors play critical roles in the development and acquisition of the specific functions of tissueresident macrophages (10, 11).”
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Okabe, Y. (2018) · International Immunology · doi:10.1093/intimm/dxy019 · Cited by 20
Hong, J. P., Reynoso, G. V., Andhey, P. S., Swain, A., Turner, J. S., Boon, A. C. M., Krammer, F., Ellebedy, A. H., Zanini, F., Artyomov, M. N., et al. (2020) · Cell Reports Medicine · doi:10.1016/j.xcrm.2020.100035 · Cited by 17
“Clustered with the Ccr2-expressing monocytes were differentiating monocytes expressing Spic, a marker of red pulp macrophages 19 (Figures S3H and S3I).”
Transcriptome Reprogramming of CD11b+ Bone Marrow Cells by Pancreatic Cancer Extracellular Vesicles
Maia, J., Otake, A. H., Poças, J., Carvalho, A. S., Beck, H. C., Magalhães, A., Matthiesen, R., Moraes, M. C. S., & Costa‐Silva, B. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.592518 · Cited by 17
Myelodysplastic syndrome macrophages have aberrant iron storage and heme oxygenase-1 expression
Nybakken, G. E., & Gratzinger, D. A. (2016) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.3109/10428194.2015.1121259 · Cited by 17
“Heme-mediated derepression of HO1 expression promotes monocyte differentiation into BM iron-recycling macrophages,[36] providing a potential mechanism for coupled increases in HO1 expression and increased macrophage infiltrates in the setting of inefficient erythropoiesis.”
BackgroundA systematic review on fluoride-induced epigenetic toxicity in mammals
Balasubramanian, S., & Perumal, E. (2022) · Critical Reviews in Toxicology · doi:10.1080/10408444.2022.2122771 · Cited by 16
Chromatin Remodeling in Monocyte and Macrophage Activation
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“BMP4 induction is that heme was accumulated in macrophages after erythrophagocytosis and promoted the degradation of BACH1 that inhibits Spic expression, therefore, Spic was induced to facilitate GDF15 and BMP4 expression (14, 52).”
BackgroundTranscriptional repression shapes the identity and function of tissue macrophages
Bene, K., Halász, L., & Nagy, L. (2021) · FEBS Open Bio · doi:10.1002/2211-5463.13269 · Cited by 15
Schaefer, R. E. M., Callahan, R. C., Atif, S. M., Orlicky, D. J., Cartwright, I. M., Fontenot, A. P., Colgan, S. P., & Onyiah, J. C. (2021) · Mucosal Immunology · doi:10.1038/s41385-021-00474-8 · Cited by 14
“2f).(25,32) Moreover, when we treated these macrophages ex vivo with LPS we noted a similar inhibition of LPS induced inflammatory gene expression in these CoPP exposed intestinal macrophages (Fig.”
MethodOxidative battles in tuberculosis: walking the ferroptotic tightrope
Araújo‐Pereira, M., & Andrade, B. B. (2025) · Trends in Immunology · doi:10.1016/j.it.2025.02.009 · Cited by 16
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Generating tissue-resident macrophages from pluripotent stem cells: Lessons learned from microglia
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Doty, R. T., Fan, X., Young, D. J., Liang, J. A., Singh, K., Pakbaz, Z., Desmond, R. G., Young-Baird, S. K., Chandrasekharappa, S. C., Donovan, F. X., et al. (2022) · Blood · doi:10.1182/blood.2021013507 · Cited by 16
Role of long noncoding RNAs in diabetes-associated peripheral arterial disease
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“Simplisti-cally, MΦs can switch between two phenotypes: M1-like (pro-inflammatory) and M2-like (anti-inflammatory or tissue-repairing), although several other functional and disease-relevant MΦ subtypes have been identified [117–119].”
BackgroundImmunoregulation role of the erythroid cells
Niu, C., & Zhang, J. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1466669 · Cited by 14
Long-term fasting and its influence on inflammatory biomarkers: A comprehensive scoping review
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“Additionally, the transcription factor SPIC, involved in macrophage differentiation, may regulate the immune response in adipose tissue during fasting (Fazeli et al., 2020; Haldar et al., 2014).”
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“The EKLF- subpopulations have enriched expression of the transcription factors Spi-C (Spic), Maf, and Nr1h3 (Figures 3C and 4A) each of which are implicated in EBI macrophage function (Kohyama et al., 2009; Kusakabe et al., 2011; Haldar et al., 2014; Zhao et al., 2021).”
BackgroundRegulation of heme biosynthesis and transport in metazoa
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Notes from the Underground: Heme Homeostasis in C. elegans
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Metabolic adaptation of macrophages in chronic diseases
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Prenatal Development and Function of Human Mononuclear Phagocytes
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Human TLR8 induces inflammatory bone marrow erythromyeloblastic islands and anemia in SLE-prone mice
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“Transcription factors previously associated with EMBI macrophages, Nr1h3 , SpiC and Maf (Kusakabe et al, 2011; Haldar et al, 2014; Li et al, 2019) were found only in clusters M φ 2 and M φ 4 (Table S3).”
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Hematoma Resolution In Vivo Is Directed by Activating Transcription Factor 1
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Microenvironmental dynamics in steady-state and stress erythropoiesis
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“12,13 A study showed that free heme mediated macrophage polarization and shaped the expression of M1 and M2 markers.”
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Homeostatic control of energy metabolism by monocyte-derived macrophages
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“Heme, an Fe-containing protopor-phyrin used as prosthetic group of hemoglobin, induces the genetic program supporting the development of Fe-recycling macrophages (Haldar et al, 2014).”
Complex Interactions in Regulation of Haematopoiesis—An Unexplored Iron Mine
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Metadata
- 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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