Role for Spi-C in the development of red pulp macrophages and splenic iron homeostasis

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Abstract
Red pulp macrophages are a distinct subset of tissue macrophages found in the spleen, and are thought to be involved in removal of senescent red blood cells. Kohyama et al. this week show that Spi-C, a PU.1-related transcription factor, selectively controls the development of red pulp macrophages. Spi-C-deficient mice fail to phagocytose trapped red blood cells. This is the first report of a transcription factor controlling the development of a tissue macrophage subset, and provides an example of a disorder in iron homeostasis caused by the loss of a specific cell lineage. The PU.1-related transcription factor Spi-C controls the development of a tissue macrophage subset in the spleen involved in the removal of red blood cells. Spi-C deficient mice fail to phagocytose trapped red blood cells. Tissue macrophages comprise a heterogeneous group of cell types differing in location, surface markers and function1. Red pulp macrophages are a distinct splenic subset involved in removing senescent red blood cells2. Transcription factors such as PU.1 (also known as Sfpi1 ) and C/EBPα (Cebpa) have general roles in myelomonocytic development3,4, 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.