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Heme-Mediated SPI-C Induction Promotes Monocyte Differentiation into Iron-Recycling Macrophages

Haldar, Malay and Kohyama, Masako and So, Alex Yick-Lun and Wumesh, K. C. and Wu, Xiaodi and Briseño, Carlos G. and Satpathy, Ansuman T. and Kretzer, Nicole M. and Arase, Hisashi and Rajasekaran, Namakkal S. and Wang, Li and Egawa, Takeshi and Igarashi, Kazuhiko and Baltimore, David and Murphy, Theresa L. and Murphy, Kenneth M. (2014) Heme-Mediated SPI-C Induction Promotes Monocyte Differentiation into Iron-Recycling Macrophages. Cell, 156 (6). pp. 1223-1234. ISSN 0092-8674. PMCID PMC4010949. doi:10.1016/j.cell.2014.01.069.

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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.

Item Type:Article
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URLURL TypeDescription CentralArticle
Baltimore, David0000-0001-8723-8190
Additional Information:© 2014 Elsevier Inc. Received: May 1, 2013. Revised: November 29, 2013. Accepted: January 23, 2014. Published: March 13, 2014. This work was supported by the Howard Hughes Medical Institute (K.M.M.), Department of Defence (W81XWH-09-1-0185 to K.M.M.), National Institutes of Health (AI076427-02 to K.M.M., T32 CA 9547-27 to M.H., 1K08AI106953 to M.H., K99HL118754 to A.Y.-L.S., and 5R01AI093531 to D.B.), the Physician Scientist Training Program in the Department of Pathology and Immunology at the Washington University School of Medicine (M.H.), and the American Heart Association (12PRE8610005 to A.T.S. and 12PRE12050419 to W.K.).
Funding AgencyGrant Number
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Department of DefenceW81XWH-09-1-0185
NIHT32 CA 9547-27
Washington University School of Medicine Physician Scientist Training ProgramUNSPECIFIED
American Heart Association12PRE8610005
American Heart Association12PRE12050419
Issue or Number:6
PubMed Central ID:PMC4010949
Record Number:CaltechAUTHORS:20140418-092054237
Persistent URL:
Official Citation:Malay Haldar, Masako Kohyama, Alex Yick-Lun So, Wumesh KC, Xiaodi Wu, Carlos G. Briseño, Ansuman T. Satpathy, Nicole M. Kretzer, Hisashi Arase, Namakkal S. Rajasekaran, Li Wang, Takeshi Egawa, Kazuhiko Igarashi, David Baltimore, Theresa L. Murphy, Kenneth M. Murphy, Heme-Mediated SPI-C Induction Promotes Monocyte Differentiation into Iron-Recycling Macrophages, Cell, Volume 156, Issue 6, 13 March 2014, Pages 1223-1234, ISSN 0092-8674, (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:45050
Deposited By: Ruth Sustaita
Deposited On:18 Apr 2014 18:26
Last Modified:10 Nov 2021 16:59

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