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

Abstract

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.

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Figure 1: Spic -/- mice have a selective loss of red pulp macrophages.
Figure 2: Spic -/- mice have a cell-autonomous defect in red pulp macrophages.
Figure 3: Spic -/- mice have increased splenic iron stores.
Figure 4: Spi-C regulates Vcam1 expression.

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Acknowledgements

This work was supported by the Howard Hughes Medical Institute (K.M.M.), and the Burroughs Wellcome Fund Career Award for Medical Scientists (B.T.E.).

Author Contributions M.K. designed experiments, analysed and interpreted results, and wrote the manuscript; W.I. sorted cells and did retrovirus experiments; B.T.E. contributed gene expression microarray data for mouse tissues; P.R.W. did B cell analysis; K.H. did T cell differentiation analysis; M.A.F. provided Cd47-/- mice; T.L.M. did EMSA; and K.M.M. directed the study and wrote the manuscript.

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Correspondence to Kenneth M. Murphy.

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This file contains Supplementary Methods, Supplementary Figures 1-10 with legends, Supplementary Tables 1-2 and Supplementary References. (PDF 6264 kb)

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Kohyama, M., Ise, W., Edelson, B. et al. Role for Spi-C in the development of red pulp macrophages and splenic iron homeostasis. Nature 457, 318–321 (2009). https://doi.org/10.1038/nature07472

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