TY - JOUR
T1 - Heme-mediated SPI-C induction promotes monocyte differentiation into iron-recycling macrophages
AU - Haldar, Malay
AU - Kohyama, Masako
AU - So, Alex Yick Lun
AU - Kc, Wumesh
AU - Wu, Xiaodi
AU - Briseño, Carlos G.
AU - Satpathy, Ansuman T.
AU - Kretzer, Nicole M.
AU - Arase, Hisashi
AU - Rajasekaran, Namakkal S.
AU - Wang, Li
AU - Egawa, Takeshi
AU - Igarashi, Kazuhiko
AU - Baltimore, David
AU - Murphy, Theresa L.
AU - Murphy, Kenneth M.
N1 - Funding Information:
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.).
PY - 2014/3/13
Y1 - 2014/3/13
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84896366680&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2014.01.069
DO - 10.1016/j.cell.2014.01.069
M3 - Article
C2 - 24630724
AN - SCOPUS:84896366680
SN - 0092-8674
VL - 156
SP - 1223
EP - 1234
JO - Cell
JF - Cell
IS - 6
ER -