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Published March 13, 2014 | Version Accepted Version + Supplemental Material
Journal Article Open

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

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Abstract

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.

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.).

Attached Files

Accepted Version - nihms571100.pdf

Supplemental Material - mmc1.pdf

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mmc1.pdf

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Additional details

Identifiers

PMCID
PMC4010949
Eprint ID
45050
Resolver ID
CaltechAUTHORS:20140418-092054237

Funding

Howard Hughes Medical Institute (HHMI)
Department of Defence
W81XWH-09-1-0185
NIH
AI076427-02
NIH
T32 CA 9547-27
NIH
1K08AI106953
NIH
K99HL118754
NIH
5R01AI093531
Washington University School of Medicine Physician Scientist Training Program
American Heart Association
12PRE8610005
American Heart Association
12PRE12050419

Dates

Created
2014-04-18
Created from EPrint's datestamp field
Updated
2021-11-10
Created from EPrint's last_modified field