XPR1 regulates fetal liver macrophage development, identity, and pyrenocyte clearance.

Inorganic phosphate (Pi) is an essential nutrient for all organisms. It has critical functions in lipid and nucleic acid synthesis, protein signaling and bone growth. Loss-of-function mutations in Pi transporters lead to embryonic and neonatal lethality. Here, we show that the only known Pi exporter, XPR1, is critical for the development of fetal macrophages in the liver and the spleen. Single-cell RNA-seq and flow cytometry analyses in conditional mice lacking Xpr1 in hematopoietic and/or CD206+ cells revealed loss of the Kupffer cell transcriptional program and a shift in the development of fetal liver monocytes towards an interferon-activated monocyte/macrophage state. Functionally, Xpr1 deficiency in embryos led to a failure to clear nuclei expelled from erythroblasts. In adulthood, splenic red pulp and bone marrow macrophages were also reduced upon loss of intrinsic Xpr1. Collectively, these findings reveal that XPR1 is required for the development, identity, and function of macrophages involved in erythropoiesis.