Heme-mediated SPI-C induction promotes monocyte differentiation into iron-recycling macrophages

Area of Science:

• Immunology
• Hematology
• Cell Biology

Background:

• Splenic red pulp macrophages (RPM) are crucial for clearing aged red blood cells and recycling iron.
• The transcription factor SPI-C is essential for RPM development, but its inducing stimulus was unknown.
• Heme is a key metabolite generated during erythrocyte degradation.

Purpose of the Study:

• To identify the physiological stimulus that induces SPI-C expression in macrophages.
• To elucidate the role of heme in regulating macrophage development and iron homeostasis.
• To investigate the mechanism by which heme controls SPI-C expression.

Main Methods:

• Investigated SPI-C expression in splenic red pulp macrophages (RPM) and bone marrow macrophages (BMM).
• Utilized mouse models of pathologic hemolysis to study macrophage responses to excess heme.
• Analyzed the interaction between heme, the transcriptional repressor BACH1, and SPI-C expression using proteasome inhibition and BACH1 degradation studies.

Main Results:

• Heme was identified as the inducer of SPI-C expression, regulating both RPM and BMM development.
• Pathologic hemolysis led to RPM and BMM loss but induced SPI-C in monocytes to replenish these populations.
• Heme promotes SPI-C expression by causing proteasome-dependent degradation of the inhibitor BACH1, a process dependent on specific motifs within BACH1.

Conclusions:

• This study demonstrates metabolite-driven differentiation of a tissue-resident macrophage subset, specifically RPM and BMM, by heme.
• Heme-induced degradation of BACH1 is a critical step for SPI-C derepression and subsequent macrophage development.
• These findings offer novel insights into the regulation of iron homeostasis and macrophage biology.