Role for Spi-C in the development of red pulp macrophages and splenic iron homeostasis.
Tissue macrophages comprise a heterogeneous group of cell types differing in location, surface markers and function. Red pulp macrophages are a distinct splenic subset involved in removing senescent red blood cells. Transcription factors such as PU.1 (also known as Sfpi1) and C/EBPalpha (Cebpa) have general roles in myelomonocytic development, but the transcriptional basis for producing tissue macrophage subsets remains unknown. Here we show that Spi-C (encoded by Spic), a PU.1-related transcription factor, selectively controls the development of red pulp macrophages. Spi-C is highly expressed in red pulp macrophages, but not monocytes, dendritic cells or other tissue macrophages. Spic(-/-) mice have a cell-autonomous defect in the development of red pulp macrophages that is corrected by retroviral Spi-C expression in bone marrow cells, but have normal monocyte and other macrophage subsets. Red pulp macrophages highly express genes involved in capturing circulating haemoglobin and in iron regulation. Spic(-/-) mice show normal trapping of red blood cells in the spleen, but fail to phagocytose these red blood cells efficiently, and develop an iron overload localized selectively to splenic red pulp. Thus, Spi-C controls development of red pulp macrophages required for red blood cell recycling and iron homeostasis.
Kohyama
Masako
M
Department of Pathology and Immunology, Washington University School of Medicine, 660 S. Euclid Avenue, St Louis, Missouri 63110, USA.
Ise
Wataru
W
Edelson
Brian T
BT
Wilker
Peter R
PR
Hildner
Kai
K
Mejia
Carlo
C
Frazier
William A
WA
Murphy
Theresa L
TL
Murphy
Kenneth M
KM
D000818:Animals; D002452:Cell Count; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004912:Erythrocytes / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D006706:Homeostasis; D007501:Iron / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000502:physiology*; D051379:Mice; D010587:Phagocytosis; D013154:Spleen / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
D004268:DNA-Binding Proteins; C423918:Spic protein, mouse; D019010:Vascular Cell Adhesion Molecule-1; D007501:Iron