The DOI matches its Crossref record; 48 of the 48 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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
“From iron recycling in the spleen30, 31 and synaptic pruning in the brain32 to thermoregulation in brown fat33 and hematopoietic control in the bone marrow and spleen34, macrophages are remarkably adaptable.”
From Abandoning M1/M2 for a Network Model of Macrophage Function (2016) · cites this paper as [30]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Protective and pathogenic functions of macrophage subsets
Murray, P. J., & Wynn, T. A. (2011) · Nature Reviews Immunology · doi:10.1038/nri3073 · Cited by 5,269 · cited 4×
“Macrophages in various tissues have distinct tissue-specific homeostatic roles, such as osteoclasts that regulate bone morphogenesis, alveolar macrophages that regulate pulmonary surfactant turnover, and splenic red pulp macrophages (RPM) that regulate erythrocyte degradation and iron recycling (Pollard, 2009; Gordon…”
InfluentialMonocyte and macrophage heterogeneity
Gordon, S., & Taylor, P. R. (2005) · Nature Reviews Immunology · doi:10.1038/nri1733 · Cited by 5,190 · cited 2×
“Macrophages in various tissues have distinct tissue-specific homeostatic roles, such as osteoclasts that regulate bone morphogenesis, alveolar macrophages that regulate pulmonary surfactant turnover, and splenic red pulp macrophages (RPM) that regulate erythrocyte degradation and iron recycling (Pollard, 2009; Gordon…”
A Lineage of Myeloid Cells Independent of Myb and Hematopoietic Stem Cells
Schulz, C., Perdiguero, E. G., Chorro, L., Szabo-Rogers, H., Cagnard, N., Kierdorf, K., Prinz, M., Wu, B., Jacobsen, S. E. W., Pollard, J. W., et al. (2012) · Science · doi:10.1126/science.1219179 · Cited by 2,578
Hashimoto, D., Chow, A., Noizat, C., Teo, P., Beasley, M. B., Leboeuf, M., Becker, C. D., See, P., Price, J., Lucas, D., et al. (2013) · Immunity · doi:10.1016/j.immuni.2013.04.004 · Cited by 2,311 · cited 2×
“Recent studies have questioned the monocyte origin of macrophages, instead suggesting that most tissue-resident macrophages are maintained by local proliferation (Schulz et al., 2012a; Hashimoto et al., 2013).”
The Immunological Genome Project: networks of gene expression in immune cells
The Immunological Genome Project Consortium, Heng, T. S. P., Painter, M. W., Elpek, K., Lukacs-Kornek, V., Mauermann, N., Turley, S. J., Koller, D., Kim, F. S., Wagers, A. J., et al. (2008) · Nature Immunology · doi:10.1038/ni1008-1091 · Cited by 1,864 · cited 1×
“Agonist-mediated activation of the nuclear receptors NR1D1, PPARγ, LXRα, and RXRα (Heng and Painter, 2008), which are each highly expressed in RPM, also failed to induce SPIC-EGFP (Figure S3B–S3D).”
Identification of the haemoglobin scavenger receptor
Kristiansen, M., Graversen, J. H., Jacobsen, C., Sonne, O., Hoffman, H.-J., Law, S. K. A., & Moestrup, S. K. (2001) · Nature · doi:10.1038/35051594 · Cited by 1,712 · cited 2×
“RPM actively accrue heme via erythrophagocytosis, CD163 receptor-mediated uptake of circulating hemoglobin-haptoglobin complexes, and CD91 receptor-mediated uptake of circulating heme-hemopexin complexes (Hvidberg et al., 2005; Kristiansen et al., 2001; Bratosin et al., 1998).”
Jenkins, S. J., Rückerl, D., Cook, P. C., Jackson-Jones, L. H., Finkelman, F. D., van Rooijen, N., MacDonald, A. S., & Allen, J. E. (2011) · Science · doi:10.1126/science.1204351 · Cited by 1,404 · cited 1×
“These tissue-resident macrophages are thought to be maintained by the differentiation of circulating monocytes and local proliferation (Landsman and Jung, 2007; Jenkins et al., 2011; Hume, 2008).”
MACROPHAGE RECEPTORS AND IMMUNE RECOGNITION
Taylor, P. R., Martínez‐Pomares, L., Stacey, M. A., Lin, H.-H., Brown, G. D., & Gordon, S. (2005) · Annual Review of Immunology · doi:10.1146/annurev.immunol.23.021704.115816 · Cited by 1,366 · cited 2×
“Macrophages in various tissues have distinct tissue-specific homeostatic roles, such as osteoclasts that regulate bone morphogenesis, alveolar macrophages that regulate pulmonary surfactant turnover, and splenic red pulp macrophages (RPM) that regulate erythrocyte degradation and iron recycling (Pollard, 2009; Gordon…”
Reduced stress defense in heme oxygenase 1-deficient cells
Poss, K. D., & Tonegawa, S. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.20.10925 · Cited by 1,294
Trophic macrophages in development and disease
Pollard, J. W. (2009) · Nature Reviews Immunology · doi:10.1038/nri2528 · Cited by 1,178 · cited 4×
“Macrophages in various tissues have distinct tissue-specific homeostatic roles, such as osteoclasts that regulate bone morphogenesis, alveolar macrophages that regulate pulmonary surfactant turnover, and splenic red pulp macrophages (RPM) that regulate erythrocyte degradation and iron recycling (Pollard, 2009; Gordon…”
Influential
Cited by
Sorted by citations
Tissue-Resident Macrophage Enhancer Landscapes Are Shaped by the Local Microenvironment
Lavin, Y., Winter, D., Blecher-Gonen, R., David, E., Keren-Shaul, H., Merad, M., Jung, S., & Amit, I. (2014) · Cell · doi:10.1016/j.cell.2014.11.018 · Cited by 2,167
“Heme has been shown to induce Spi-c, a transcription factor (TF) important for red pulp macrophage development (Haldar et al., 2014; Kohyama et al., 2009).”
BackgroundResultResolving the fibrotic niche of human liver cirrhosis at single-cell level
Ramachandran, P., Dobie, R., Wilson-Kanamori, J. R., Dora, E. F., Henderson, B. E. P., Luu, N. T., Portman, J. R., Matchett, K. P., Brice, M., Marwick, J. A., et al. (2019) · Nature · doi:10.1038/s41586-019-1631-3 · Cited by 1,784
Origin and functions of tissue macrophages
Epelman, S., Lavine, K. J., & Randolph, G. J. (2014) · Immunity · doi:10.1016/j.immuni.2014.06.013 · Cited by 1,585
A Red carpet for iron metabolism
Muckenthaler, M. U., Rivella, S., Hentze, M. W., & Galy, B. (2017) · Cell · doi:10.1016/j.cell.2016.12.034 · Cited by 1,319
Cross-tissue immune cell analysis reveals tissue-specific features in humans
Conde, C. D., Xu, C., Jarvis, L. B., Rainbow, D. B., Wells, S. B., Gomes, T., Howlett, S. K., Suchánek, O., Polański, K., King, H. W., et al. (2022) · Science · doi:10.1126/science.abl5197 · Cited by 1,246
“Erythrophagocytic macrophages, including red pulp macrophages and Kupffer cells, mainly populated the spleen and liver, as expected, and shared high expression of CD5L, SCL40A1 and the transcription factor SPIC (32).”
BackgroundMacrophages: Development and Tissue Specialization
Varol, C., Mildner, A., & Jung, S. (2015) · Annual Review of Immunology · doi:10.1146/annurev-immunol-032414-112220 · Cited by 962
“Yet, in the case of iron overload toxicity, which acutely eliminates RPMs, heme moieties can trigger Spi-C expression in monocytes, and these cells might contribute to the reestablishment of the RPM compartment (187).”
BackgroundThe Phagocytic Function of Macrophage-Enforcing Innate Immunity and Tissue Homeostasis
Hirayama, D., Iida, T., & Nakase, H. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms19010092 · Cited by 927
“Red pulp macrophages clear damaged blood cells, recycle iron [73,74], and catabolize heme [75].”
BackgroundNew insights into the multidimensional concept of macrophage ontogeny, activation and function
Ginhoux, F., Schultze, J. L., Murray, P. J., Ochando, J., & Biswas, S. K. (2015) · Nature Immunology · doi:10.1038/ni.3324 · Cited by 858
Macrophage heterogeneity in tissues: phenotypic diversity and functions
Gordon, S., Plüddemann, A., & Martínez, F. O. (2014) · Immunological Reviews · doi:10.1111/imr.12223 · Cited by 742
“Reflecting their major function in clearance of senescent erythrocytes, a subset of F4/80 red pulp macrophages respond to heme by induction of a specific transcription factor, Spi-C and express properties associated with heme catabolism and iron storage and reutilization (76).”
BackgroundMacrophages and cancer: from mechanisms to therapeutic implications
Ostuni, R., Kratochvill, F., Murray, P. J., & Natoli, G. (2015) · Trends in Immunology · doi:10.1016/j.it.2015.02.004 · Cited by 709
Regulation of macrophage development and function in peripheral tissues
Lavin, Y., Mortha, A., Rahman, A., & Merad, M. (2015) · Nature Reviews Immunology · doi:10.1038/nri3920 · Cited by 680
Macrophages in health and disease
Park, M. D., Silvin, A., Ginhoux, F., & Merad, M. (2022) · Cell · doi:10.1016/j.cell.2022.10.007 · Cited by 644
Tissue biology perspective on macrophages
Okabe, Y., & Medzhitov, R. M. (2015) · Nature Immunology · doi:10.1038/ni.3320 · Cited by 651
Drakesmith, H., Nemeth, E., & Ganz, T. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.09.006 · Cited by 638
“SpiC activity is normally repressed by Bach1; heme causes Bach1 degradation and derepresses SpiC in monocytes, leading to their differentiation into red pulp macrophages expressing ferroportin and heme-oxygenase-1 (Haldar et al., 2014).”
BackgroundTissue macrophages: heterogeneity and functions
Gordon, S., & Plüddemann, A. (2017) · BMC Biology · doi:10.1186/s12915-017-0392-4 · Cited by 630
“They recycle iron [46] and catabolise haem [47], an inducer of Spi-C, a transcription factor found also in other macrophages implicated in erythrocyte turnover.”
BackgroundPhysiology and diseases of tissue-resident macrophages
Lazarov, T., Juarez-Carreño, S., Cox, N., & Geissmann, F. (2023) · Nature · doi:10.1038/s41586-023-06002-x · Cited by 571
Establishment and Maintenance of the Macrophage Niche
Guilliams, M., Thierry, G. R., Bonnardel, J., & Bajenoff, M. (2020) · Immunity · doi:10.1016/j.immuni.2020.02.015 · Cited by 512
Molecular control of activation and priming in macrophages
Glass, C. K., & Natoli, G. (2015) · Nature Immunology · doi:10.1038/ni.3306 · Cited by 538
Abandoning M1/M2 for a Network Model of Macrophage Function
Nahrendorf, M., & Swirski, F. K. (2016) · Circulation Research · doi:10.1161/circresaha.116.309194 · Cited by 525
Metabolism of tissue macrophages in homeostasis and pathology
Wculek, S. K., Dunphy, G., Heras-Murillo, I., Mastrangelo, A., & Sancho, D. (2022) · Cellular & Molecular Immunology · doi:10.1038/s41423-021-00791-9 · Cited by 501
Fibroblast-macrophage reciprocal interactions in health, fibrosis, and cancer
Buechler, M. B., Fu, W., & Turley, S. J. (2021) · Immunity · doi:10.1016/j.immuni.2021.04.021 · Cited by 494
Chen, Y., Yin, J., Li, W., Li, H.-J., Chen, D., Zhang, C., Lv, J., Wang, Y., Li, X., Li, J., et al. (2020) · Cell Research · doi:10.1038/s41422-020-0374-x · Cited by 478
On Iron Metabolism and Its Regulation
Vogt, A. S., Arsiwala, T., Mohsen, M. O., Vogel, M., Manolova, V., & Bachmann, M. F. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22094591 · Cited by 505
“The macrophage lineage with the capacity of erythrophagocytosis originates essentially from bone marrow derived monocyte progenitors [60].”
BackgroundOn-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver
Theurl, I., Hilgendorf, I., Nairz, M., Tymoszuk, P., Haschka, D., Asshoff, M., He, S., Gerhardt, L. M. S., Holderried, T. A. W., Seifert, M., et al. (2016) · Nature Medicine · doi:10.1038/nm.4146 · Cited by 412
Macrophages and lipid metabolism
Remmerie, A., & Scott, C. L. (2018) · Cellular Immunology · doi:10.1016/j.cellimm.2018.01.020 · Cited by 451
Macrophages and Iron Metabolism
Soares, M. P., & Hamza, I. (2016) · Immunity · doi:10.1016/j.immuni.2016.02.016 · Cited by 401
“Heme inducesmonocyte differentiation into the erythrophagocytic macrophage lineage via activation of a signal transduction pathway releasing Bach1 and allowing the activation of SPI-C Immunity 44, March 15, 2016 ª2016 Elsevier Inc. 497 (Haldar et al., 2014; Kohyama et al., 2009).”
BackgroundInfluentialAmit, I., Winter, D. R., & Jung, S. (2015) · Nature Immunology · doi:10.1038/ni.3325 · Cited by 416
Liver macrophages in health and disease
Guilliams, M., & Scott, C. L. (2022) · Immunity · doi:10.1016/j.immuni.2022.08.002 · Cited by 395
Fetal monocytes and the origins of tissue-resident macrophages
Hoeffel, G., & Ginhoux, F. (2018) · Cellular Immunology · doi:10.1016/j.cellimm.2018.01.001 · Cited by 431
Aryl hydrocarbon receptor Controls Monocyte Differentiation into dendritic Cells versus Macrophages
Goudot, C., Coillard, A., Villani, A.-C., Gueguen, P., Cros, A., Sarkizova, S., Tang-Huau, T.-L., Bohec, M., Baulande, S., Hacohen, N., et al. (2017) · Immunity · doi:10.1016/j.immuni.2017.08.016 · Cited by 382
“Macrophages derive from embryonic precursors whose differentiation is strongly imprinted by the micro-environment (Gosselin et al., 2014; Haldar et al., 2014; Lavin et al., 2014; Okabe and Medzhitov, 2014).”
BackgroundA cellular and spatial map of the choroid plexus across brain ventricles and ages
Dani, N., Herbst, R. H., McCabe, C., Green, G. S., Kaiser, K., Head, J. P., Cui, J., Shipley, F. B., Jang, A., Dionne, D., et al. (2021) · Cell · doi:10.1016/j.cell.2021.04.003 · Cited by 388
Tissue macrophages: origin, heterogenity, biological functions, diseases and therapeutic targets
Guan, F., Wang, R., Yi, Z., Luo, P., Liu, W., Xie, Y., Liu, Z., Xia, Z., Zhang, H., & Cheng, Q. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02124-y · Cited by 371
Iron in infection and immunity
Nairz, M., & Weiss, G. (2020) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2020.100864 · Cited by 359
Ontogeny of Tissue-Resident Macrophages
Hoeffel, G., & Ginhoux, F. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00486 · Cited by 364
Tissue‐resident macrophages: then and now
Davies, L. C., & Taylor, P. R. (2015) · Immunology · doi:10.1111/imm.12451 · Cited by 348
Molecular and epigenetic basis of macrophage polarized activation
Porta, C., Riboldi, E., Ippolito, A., & Sica, A. (2015) · Seminars in Immunology · doi:10.1016/j.smim.2015.10.003 · Cited by 334
Revisiting Mouse Peritoneal Macrophages: Heterogeneity, Development, and Function
Cassado, A. D. A., D’Império Lima, M. R., & Bortoluci, K. R. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00225 · Cited by 315
“Heme has been shown to induce Spi-c, a transcription factor important for red pulp macrophage development (81, 82).”
BackgroundThe Role of Iron Regulation in Immunometabolism and Immune-Related Disease
Cronin, S. J. F., Woolf, C. J., Weiss, G., & Penninger, J. M. (2019) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2019.00116 · Cited by 299
“Interestingly, heme promotes monocyte differentiation into ironrecycling macrophages by inducing the master transcription factor for macrophage differentiation SPI-C, through direction inhibition of its repressor BACH1 (Haldar et al., 2014).”
BackgroundMacrophages: The Road Less Traveled, Changing Anticancer Therapy
Guerriero, J. L. (2018) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2018.03.006 · Cited by 300
“During homeostatic adaptations, macrophages of different phenotypes can also be recruited from the monocytes reservoirs of blood, spleen and bone marrow [27], but also from resident progenitors or through local proliferation [25, 40, 46, 47].”
BackgroundPhagocytosis imprints heterogeneity in tissue-resident macrophages
A-González, N., Quintana, J. A., Garcı́a-Silva, S., Mazariegos, M. S., de la Aleja, A. G., Nicolás-Ávila, J. Á., Walter, W., Adrover, J. M., Crainiciuc, G., Kuchroo, V. K., et al. (2017) · The Journal of Experimental Medicine · doi:10.1084/jem.20161375 · Cited by 293
Pisu, D., Huang, L., Grenier, J. K., & Russell, D. G. (2020) · Cell Reports · doi:10.1016/j.celrep.2019.12.033 · Cited by 289
“Spi-C has been shown to be upregulated in a heme-dependent manner in splenic red pulp macrophages that are required to degrade senescent erythrocytes and recycle heme-associated iron (Haldar et al., 2014).”
Tissue macrophage identity and self‐renewal
Gentek, R., Molawi, K., & Sieweke, M. H. (2014) · Immunological Reviews · doi:10.1111/imr.12224 · Cited by 288
“Similarly, RPM in the spleen only receive minimal input from circulating monocytes or other BM-derived cells over prolonged observation periods (17, 19, 20), but monocytes can differentiate into resident RPMs in significant numbers under severe challenge conditions such as hemolysis (10).”
BackgroundInfluentialResident and Monocyte-Derived Macrophages in Cardiovascular Disease
Honold, L., & Nahrendorf, M. (2018) · Circulation Research · doi:10.1161/circresaha.117.311071 · Cited by 283
“macrophages, which express the heme-induced transcription factor Spi-C that allows them to manage large amounts of iron.(13,14)”
Vinchi, F., Costa da Silva, M., Ingoglia, G., Petrillo, S., Brinkman, N., Zuercher, A., Cerwenka, A., Tolosano, E., & Muckenthaler, M. U. (2016) · Blood · doi:10.1182/blood-2015-08-663245 · Cited by 269
“This process is increased during pathologic hemolysis.(57) Here we demonstrate that heme additionally affects the phenotype of differentiated macrophages.”
From the Cradle to the Grave: The Role of Macrophages in Erythropoiesis and Erythrophagocytosis
Klei, T. R. L., Meinderts, S. M., van den Berg, T. K., & van Bruggen, R. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00073 · Cited by 279
Lund, H., Pieber, M., Parsa, R., Han, J., Grommisch, D., Ewing, E., Kular, L., Needhamsen, M., Espinosa, A., Nilsson, E., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-07295-7 · Cited by 249
Ontogeny and Polarization of Macrophages in Inflammation: Blood Monocytes Versus Tissue Macrophages
Dey, A., Allen, J., & Hankey-Giblin, P. A. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00683 · Cited by 254
Tunable Supramolecular Hydrogels for Selection of Lineage-Guiding Metabolites in Stem Cell Cultures
Alakpa, E. V., Jayawarna, V., Lampel, A., Burgess, K., West, C. C., Bakker, S. C. J., Roy, S., Javid, N., Fleming, S., Lamprou, D. A., et al. (2016) · Chem · doi:10.1016/j.chempr.2016.07.001 · Cited by 211
Gautier, E. L., Ivanov, S., Williams, J. W., Huang, S. C., Marcelin, G., Fairfax, K. C., Wang, P. L., Francis, J. S., Leone, P., Wilson, D. B., et al. (2014) · The Journal of Experimental Medicine · doi:10.1084/jem.20140570 · Cited by 210
“…Spi-C is selectively expressed by red pulp macrophages, and it is essential for sustenance of this population, apparently due to its role in coordinating gene expression that facilitates handling of iron in macrophages that recycle aged erythrocytes (Kohyama et al., 2009; Haldar et al., 2014).”
BackgroundBriseño, C. G., Haldar, M., Kretzer, N. M., Wu, X., Theisen, D. J., Wumesh, K. C., Durai, V., Grajales‐Reyes, G. E., Iwata, A., Bagadia, P., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.05.025 · Cited by 224
“Expression of TREML4 and NUR77 Identifies Monocytes Lacking Mo-DC Potential TREML4, a member of the triggering receptor expressed on the myeloid cells family (Ford and McVicar, 2009), is induced during heme-mediated differentiation of macrophages frommonocytes and bonemarrow (BM) progenitors (Haldar et al., 2014).”
BackgroundSelf-citationMacrophages: sentinels and regulators of the immune system
Franken, L., Schiwon, M., & Kurts, C. (2016) · Cellular Microbiology · doi:10.1111/cmi.12580 · Cited by 225
Splenic Macrophage Subsets and Their Function during Blood-Borne Infections
da Silva, H. B., Fonseca, R., Pereira, R. M., Cassado, A. D. A., Álvarez, J. M., & Lima, M. R. D. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00480 · Cited by 201
“Of note, development of RpMΦs relies on the expression of the transcription factor Spi-C, which is induced by free heme from RBC degradation (32).”
BackgroundPro-inflammatory Actions of Heme and Other Hemoglobin-Derived DAMPs
Bozza, M. T., & Jeney, V. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01323 · Cited by 214
“During pathological hemolysis, the axis formed by heme, Bach1, and Spic is critically involved in the homeostatic response to the macrophage loss.”
BackgroundMicroglia: Multitasking Specialists of the Brain
Casano, A. M., & Peri, F. (2015) · Developmental Cell · doi:10.1016/j.devcel.2015.01.018 · Cited by 209
“, 2014), while Heme, the result of erythrocyte degradation, has been shown to induce Spi-c expression in red pulp macrophage (Haldar et al., 2014).”
BackgroundIron Regulation: Macrophages in Control
Sukhbaatar, N., & Weichhart, T. (2018) · Pharmaceuticals · doi:10.3390/ph11040137 · Cited by 213
“Moreover, the number of BM macrophages and RPMs is drastically reduced in Spic−/− mice suggesting that Spi-C-mediated regulation is indispensable for iron metabolism in these cells and for protection against iron toxicity [100,105].”
BackgroundInfluentialSevenich, L. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00697 · Cited by 206
“For example, Kupffer cells and splenic macrophages were shown to share a cluster of highly expressed genes that are enriched for gene ontology (GO) annotations, such as heme and porphyrin metabolism, indicating their role in erythrocyte turnover (48, 49).”
BackgroundSingle cell analysis of M. tuberculosis phenotype and macrophage lineages in the infected lung
Pisu, D., Huang, L., Narang, V., Theriault, M. E., Lê-Bury, G., Lee, B. T. K., Lakudzala, A. E., Mzinza, D. T., Mhango, D. V., Mitini-Nkhoma, S. C., et al. (2021) · The Journal of Experimental Medicine · doi:10.1084/jem.20210615 · Cited by 199
“Diverging heme-iron responses are associated with different bacterial phenotypes in infected IM subsets The host response to iron is well-documented as a factor of significance in Mtb infection (Amaral et al., 2019; Dixon et al., 2012; Haldar et al., 2014; Mitra et al., 2019; Phelan et al., 2018; Pisu et al., 2020a),…”
BackgroundMacrophage-based cell therapies: The long and winding road
Lee, S., Kivimäe, S., Dolor, A., & Szoka, F. C. (2016) · Journal of Controlled Release · doi:10.1016/j.jconrel.2016.07.018 · Cited by 198
Heme dynamics and trafficking factors revealed by genetically encoded fluorescent heme sensors
Hanna, D. A., Harvey, R. M., Martinez-Guzman, O., Yuan, X., Chandrasekharan, B. P., Raju, G., Outten, F. W., Hamza, I., & Reddi, A. R. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1523802113 · Cited by 191
Macrophages and iron trafficking at the birth and death of red cells
Korolnek, T., & Hamza, I. (2015) · Blood · doi:10.1182/blood-2014-12-567776 · Cited by 196
“Itwas determined that SPI-C expression was activated by heme itself, via derepression by the heme-dependent transcription factor Bach1.(74) This heme/Bach1/SPI-C axis regulates the differentiation of monocytes into RES macrophages, for example, in the case of hemolysis and a sudden toxic bolus of heme to iron-recyclin…”
The Myeloid Cell Compartment—Cell by Cell
Bassler, K. E., Schulte-Schrepping, J., Warnat‐Herresthal, S., Aschenbrenner, A. C., & Schultze, J. L. (2019) · Annual Review of Immunology · doi:10.1146/annurev-immunol-042718-041728 · Cited by 200
Youssef, L. A., Rebbaa, A., Pampou, S., Weisberg, S. P., Stockwell, B. R., Hod, E. A., & Spitalnik, S. L. (2018) · Blood · doi:10.1182/blood-2017-12-822619 · Cited by 186
M2 macrophages in kidney disease: biology, therapies, and perspectives
Chen, T., Cao, Q., Wang, Y., & Harris, D. C. H. (2019) · Kidney International · doi:10.1016/j.kint.2018.10.041 · Cited by 190
“Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels
Nairz, M., Theurl, I., Swirski, F. K., & Weiss, G. (2017) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-017-1944-8 · Cited by 178
“It is well established that RPM and KC express the complete machinery for RBC clearance and heme iron recycling [72, 88, 231].”
BackgroundAdaptation and memory in immune responses
Natoli, G., & Ostuni, R. (2019) · Nature Immunology · doi:10.1038/s41590-019-0399-9 · Cited by 203
Regulation of tissue iron homeostasis: the macrophage “ferrostat”
Winn, N. C., Volk, K. M., & Hasty, A. H. (2020) · JCI Insight · doi:10.1172/jci.insight.132964 · Cited by 188
“Patsalos A, et al. The BACH1-HMOX1 regulatory axis is indispensable for proper macrophage subtype specification and skele- tal muscle regeneration.”
BackgroundInfluentialBach1: Function, Regulation, and Involvement in Disease
Zhang, X., Guo, J., Wei, X., Niu, C., Jia, M., Li, Q., & Meng, D. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/1347969 · Cited by 179
“marrow macrophages [65], and when Bach1 was overexpressed (under the control of the GATA-1 promoter) in transgenic mice, megakaryocyte maturation was significantly impaired and the animals developed thrombocytopenia, likely because Bach1 suppressed the expression of p45targeted genes such as thromboxane synthase [66].”
Hoyer, F. F., Naxerova, K., Schloss, M. J., Hulsmans, M., Nair, A. V., Dutta, P., Calcagno, D. M., Hérisson, F., Anzai, A., Sun, Y., et al. (2019) · Immunity · doi:10.1016/j.immuni.2019.10.010 · Cited by 177
“is a tissue inhabited by macrophages that experienced a prior systemic or remote stressor more or less likely to develop subsequent disease? The emerging data on tissue-specific macrophage functions (Haldar et al., 2014; Hulsmans et al., 2017; Odegaard et al., 2007; Paolicelli et al., 2011) raise manifold implications…”
BackgroundOntogeny of Tumor-Associated Macrophages and Its Implication in Cancer Regulation
Franklin, R. A., & Li, M. O. (2016) · Trends in cancer · doi:10.1016/j.trecan.2015.11.004 · Cited by 179
“However, during hemolysis and erythrocyte damage, monocytes significantly contribute to the red pulp macrophage pool [51].”
BackgroundHemolysis, free hemoglobin toxicity, and scavenger protein therapeutics
Vallelian, F., Buehler, P. W., & Schaer, D. J. (2022) · Blood · doi:10.1182/blood.2022015596 · Cited by 173
Niche signals and transcription factors involved in tissue-resident macrophage development
T’Jonck, W., Guilliams, M., & Bonnardel, J. (2018) · Cellular Immunology · doi:10.1016/j.cellimm.2018.02.005 · Cited by 173
“Other TFs linked to tissue-resident macrophage development include LXRα and SPIC, although these might be necessary for functional specialization, as no apparent defect in Kupffer cell abundance has been described in KO models involving these TFs [45,55].”
BackgroundInfluentialBuechler, M. B., Kim, K.-W., Onufer, E. J., Williams, J. W., Little, C. C., Dominguez, C. X., Li, Q., Sandoval, W. N., Cooper, J. E., Harris, C. A., et al. (2019) · Immunity · doi:10.1016/j.immuni.2019.05.010 · Cited by 156
Ferroptosis: regulation by competition between NRF2 and BACH1 and propagation of the death signal
Nishizawa, H., Yamanaka, M., & Igarashi, K. (2022) · FEBS Journal · doi:10.1111/febs.16382 · Cited by 164
Self-citationThe origins and homeostasis of monocytes and tissue‐resident macrophages in physiological situation
Zhao, Y., Zou, W., Du, J., & Zhao, Y. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.26461 · Cited by 190
From Synthesis to Utilization: The Ins and Outs of Mitochondrial Heme
Swenson, S. A., Moore, C. M., Marcero, J. R., Medlock, A. E., Reddi, A. R., & Khalimonchuk, O. (2020) · Cells · doi:10.3390/cells9030579 · Cited by 155
“For instance, as a pro-inflammatory signaling molecule, erythrocyte-derived heme can differentiate and activate macrophages for clearance of red blood cells [15].”
BackgroundPurrington, K. S., Knight, J., Dyson, G. E., Ali‐Fehmi, R., Schwartz, A. G., Boerner, J. L., & Bandyopadhyay, S. (2020) · PLoS ONE · doi:10.1371/journal.pone.0231712 · Cited by 137
“SPIC has also been shown to act as a lymphoid-specific enhancer and regulates VCAM1 [34], a gene that has been associated with progression, angiogenesis, and metastasis in breast cancer [35].”
BackgroundSynovial tissue macrophages: friend or foe?
Kurowska‐Stolarska, M., & Alivernini, S. (2017) · RMD Open · doi:10.1136/rmdopen-2017-000527 · Cited by 140
“The local differentiation of spleen red pulp macrophages requires the transcription factor BACH1 that recognises heme from erythrocyte degradation and induces their specialised iron-recycling function.(43) Retinoic acid produced by the omentum is key in the differentiation of peritoneal macrophages that function to co…”
BackgroundHuman and Mouse Mononuclear Phagocyte Networks: A Tale of Two Species?
Reynolds, G., & Haniffa, M. A. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00330 · Cited by 138
BACH transcription factors in innate and adaptive immunity
Igarashi, K., Kurosaki, T., & Roychoudhuri, R. (2017) · Nature reviews. Immunology · doi:10.1038/nri.2017.26 · Cited by 132
Self-citationHeme as a Target for Therapeutic Interventions
Immenschuh, S., Vijayan, V., Janciauskiene, S. M., & Gueler, F. (2017) · Frontiers in Pharmacology · doi:10.3389/fphar.2017.00146 · Cited by 130
Sphingosine-1-Phosphate and Macrophage Biology—How the Sphinx Tames the Big Eater
Weigert, A., Olesch, C., & Brüne, B. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01706 · Cited by 130
“These include SPI-C in progenitors of red pulp and bone marrow macrophages (29), GATA6 in peritoneal macrophages (30, 31), peroxisome proliferator-activated receptor (PPAR) in alveolar macrophages (32), SMAD transcription factors and myocyte-specific enhancer factor 2c (MEF2c) in microglia (33, 34), liver x receptor (…”
BackgroundRegulation of intracellular heme trafficking revealed by subcellular reporters
Yuan, X., Rietzschel, N., Kwon, H., Walter‐Nuno, A. B., Hanna, D. A., Phillips, J. D., Raven, E. L., Reddi, A. R., & Hamza, I. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1609865113 · Cited by 123
“GPI anchored HRP mCherry GalT (1-61) mCherry KDEL HRP”
BackgroundBai, X., Guo, Y.-R., Zhao, Z., Li, X., Dai, D.-Q., Zhang, J., Li, Y.-S., & Zhang, C. (2025) · Cancer Letters · doi:10.1016/j.canlet.2025.217772 · Cited by 140
Iron and innate antimicrobial immunity-depriving the pathogen, defending the host
Nairz, M., Dichtl, S., Schroll, A., Haschka, D., Tymoszuk, P., Theurl, I., & Weiss, G. (2018) · Journal of Trace Elements in Medicine and Biology · doi:10.1016/j.jtemb.2018.03.007 · Cited by 123
Staiano, R. I., Loffredo, S., Borriello, F., Iannotti, F. A., Piscitelli, F., Orlando, P., Secondo, A., Granata, F., Lepore, M. T., Fiorelli, A., et al. (2015) · Journal of Leukocyte Biology · doi:10.1189/jlb.3hi1214-584r · Cited by 126
“In addition, tissue-resident macrophages might be functionally different from in vitro-derived macrophages owing to their ontogeny and/or tissue-derived signals [6–10].”
Núñez, G., Sakamoto, K., & Soares, M. P. (2018) · The Journal of Immunology · doi:10.4049/jimmunol.1800325 · Cited by 115
“This occurs via different mechanisms that rely on heme transport by parasite-encoded heme-responsive gene 1 (HRG1/solute carrier family 48 member 1 or SLC48A1) or orthologous genes (72), as demonstrated for Leishmania spp. (73). and for Trypanosoma spp. (74).”
BackgroundLymphatic Endothelial Cells Are Essential Components of the Subcapsular Sinus Macrophage Niche
Mondor, I., Baratin, M., Lagueyrie, M., Saro, L., Henri, S., Gentek, R., Suerinck, D., Kastenmüller, W., Jiang, J. X., & Bajénoff, M. (2019) · Immunity · doi:10.1016/j.immuni.2019.04.002 · Cited by 125
SUMMERS, K. M., Bush, S. J., & Hume, D. A. (2020) · PLoS Biology · doi:10.1371/journal.pbio.3000859 · Cited by 114
“The transcription factor SPIC is implicated in splenic red pulp macrophage differentiation and iron homeostasis [114, 115].”
Niche-specific functional heterogeneity of intestinal resident macrophages
Viola, M. F., & Boeckxstaens, G. E. (2020) · Gut · doi:10.1136/gutjnl-2020-323121 · Cited by 122
Heme Mobilization in Animals: A Metallolipid’s Journey
Reddi, A. R., & Hamza, I. (2016) · Accounts of Chemical Research · doi:10.1021/acs.accounts.5b00553 · Cited by 122
Origin, development, and homeostasis of tissue‐resident macrophages
Haldar, M., & MURPHY, K. M. M. (2014) · Immunological Reviews · doi:10.1111/imr.12215 · Cited by 125
“RPMs and BMM degrade heme and release the heme-associated iron back into the circulation.”
BackgroundInfluentialSelf-citationThe islet-resident macrophage is in an inflammatory state and senses microbial products in blood
Ferris, S. T., Zakharov, P. N., Wan, X., Calderón, B., Artyomov, M. N., Unanue, E. R., & Carrero, J. A. (2017) · The Journal of Experimental Medicine · doi:10.1084/jem.20170074 · Cited by 118
“For example, red pulp macrophages are specialized to dispose of effete red blood cells by sensing heme and inducing Spic (Haldar et al., 2014).”
BackgroundFunctions and development of red pulp macrophages
Kurotaki, D., Uede, T., & Tamura, T. (2015) · Microbiology and Immunology · doi:10.1111/1348-0421.12228 · Cited by 121
“Heme per se, and not its metabolites, reportedly potently induces Spi-C expression in monocytes and bone marrow-derived macrophages (36).”
BackgroundIgarashi, K., & Watanabe‐Matsui, M. (2014) · The Tohoku Journal of Experimental Medicine · doi:10.1620/tjem.232.229 · Cited by 115
“In addition to the regulation of iron-related genes, Bach1 represses the expression of Spi-c, which encodes a transcription factor essential for the differentiation of macrophages dedicated for the iron recycling (e.g., red pulp macrophages) (Haldar et al. 2014).”
Self-citationTissue Immunometabolism: Development, Physiology, and Pathobiology
Man, K., Kutyavin, V. I., & Chawla, A. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.08.016 · Cited by 108
“…Kupffer cells, a transcription factor that is induced by heme and regulates the recycling of iron, provides another example of how coordination between tissue-resident immune and parenchymal cells might be orchestrated by metabolites (Haldar et al., 2014; Kohyama et al., 2009; Lavin et al., 2014).”
BackgroundIron homeostasis and disorders revisited in the sepsis
Liu, Q., Wu, J., Zhang, X., Wu, X., Zhao, Y., & Ren, J. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.01.025 · Cited by 113
Self-citationBellomo, A., Mondor, I., Spinelli, L., Lagueyrie, M., Stewart, B. J., Brouilly, N., MALISSEN, B., Clatworthy, M. R., & Bajénoff, M. (2020) · Immunity · doi:10.1016/j.immuni.2020.06.008 · Cited by 112
Development and function of tissue resident macrophages in mice
Kierdorf, K., Prinz, M., Geissmann, F., & Perdiguero, E. G. (2015) · Seminars in Immunology · doi:10.1016/j.smim.2016.03.017 · Cited by 114
Stress Erythropoiesis is a Key Inflammatory Response
Paulson, R. F., Ruan, B., Hao, S., & Chen, Y. (2020) · Cells · doi:10.3390/cells9030634 · Cited by 113
“GDF15 is a critical signal for the initiation of stress erythropoiesis and its expression is regulated by SpiC.”
BackgroundFirst we eat, then we do everything else: The dynamic metabolic regulation of efferocytosis
Trzeciak, A. J., Wang, Y., & Perry, J. S. A. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.08.001 · Cited by 109
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
