title: Heme-mediated SPI-C induction promotes monocyte differentiation into iron-recycling macrophages.
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.
authors.affiliation: Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Malay
authors.initials: M
authors.lastname: Haldar
authors.affiliation: Laboratory of Immunochemistry, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Kohyama
authors.affiliation: Department of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Alex Yick-Lun
authors.initials: AY
authors.lastname: So
authors.affiliation: Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Wumesh
authors.initials: W
authors.lastname: Kc
authors.affiliation: Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Xiaodi
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Briseño
authors.affiliation: Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Ansuman T
authors.initials: AT
authors.lastname: Satpathy
authors.affiliation: Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Kretzer
authors.affiliation: Laboratory of Immunochemistry, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Arase
authors.affiliation: Division of Cardiology and Pulmonary, Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT 84132, USA.
authors.forename: Namakkal S
authors.initials: NS
authors.lastname: Rajasekaran
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT 84132, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Egawa
authors.affiliation: Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Igarashi
authors.affiliation: Department of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: David
authors.initials: D
authors.lastname: Baltimore
authors.affiliation: Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Murphy
authors.affiliation: Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA; Howard Hughes Medical Institute, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA. Electronic address: kmurphy@wustl.edu.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Murphy
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006418:Heme / Q000378:metabolism*; D007501:Iron / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000378:metabolism*; D022423:Myeloid Cells / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000378:metabolism
chemical_list: C486316:Bach1 protein, mouse; D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; C423918:Spic protein, mouse; D006418:Heme; D007501:Iron