Heme-mediated SPI-C Induction Promotes Monocyte Differentiation into Iron-recycling Macrophages

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2014 Mar 18

PMID 24630724

Citations 201

Authors

Malay Haldar

Masako Kohyama

Alex Yick-Lun So

Wumesh Kc

Xiaodi Wu

Carlos G Briseno

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

Affiliations

Soon will be listed here.

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.

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