IRF8 and MAFB drive distinct transcriptional machineries in different resident macrophages of the central nervous system
Ayato Yamasaki1,2, Iroha Imanishi1, Kaori Tanaka3
1Division of Molecular Neuroimmunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Abstract:
The central nervous system (CNS) includes anatomically distinct macrophage populations including parenchyma microglia and CNS-associated macrophages (CAMs) localized at the interfaces like meninges and perivascular space, which play specialized roles for the maintenance of the CNS homeostasis with the help of precisely controlled gene expressions. However, the transcriptional machinery that determines their cell-type specific states of microglia and CAMs remains poorly understood. Here we show, by myeloid cell-specific deletion of transcription factors, IRF8 and MAFB, that both adult microglia and CAMs utilize IRF8 to maintain their core gene signatures, although the genes altered by IRF8 deletion are different in the two macrophage populations. By contrast, MAFB deficiency robustly affected the gene expression profile of adult microglia, whereas CAMs are almost independent of MAFB. Our data suggest that distinct transcriptional machineries regulate different macrophages in the CNS.
Insights
Distinct transcription factors regulate central nervous system (CNS) macrophages. Microglia and CNS-associated macrophages (CAMs) rely on IRF8, but only microglia significantly depend on MAFB for their unique gene expression.
Area of Science:
- Neuroimmunology
- Molecular Biology
- Cell Biology
Background:
- The central nervous system (CNS) contains specialized macrophage populations: microglia and CNS-associated macrophages (CAMs).
- These macrophages maintain CNS homeostasis through precisely controlled gene expression.
- The transcriptional regulators defining microglia and CAM states are not fully understood.
Purpose of the Study:
- To investigate the roles of transcription factors IRF8 and MAFB in regulating gene expression in adult microglia and CAMs.
- To elucidate the distinct transcriptional machinery governing these two CNS macrophage populations.
Main Methods:
- Myeloid cell-specific deletion of the transcription factors IRF8 and MAFB in adult mice.
- Analysis of gene expression profiles in microglia and CAMs following transcription factor deletion.
Main Results:
- Both microglia and CAMs require IRF8 for maintaining their core gene signatures, though the specific genes affected differ between populations.
- MAFB deficiency significantly impacts the gene expression profile of microglia but has minimal effect on CAMs.
- CAMs demonstrate a notable independence from MAFB-driven gene regulation compared to microglia.
Conclusions:
- Distinct transcriptional machineries govern the unique cell-type specific states of microglia and CAMs within the CNS.
- IRF8 is crucial for both microglia and CAMs, while MAFB plays a more specialized role primarily in microglia regulation.
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