Homozygous kinase-dead Csf1r mutation in outbred mice reveals essential and redundant functions of tissue resident macrophages.

The proliferation, differentiation, and survival of cells of the macrophage lineage depends on signals from the macrophage colony-stimulating factor receptor (CSF1R). On a C57BL/6J background homozygous kinase-dead Csf1r mutation (Csf1rE631K/E631K-E631Km/m) causes perinatal lethality. By contrast, E631Km/m mice on a mixed genetic background (C57 × BALB/c) were osteoclast-deficient/osteopetrotic and growth retarded but did not develop hydrocephalus or other major structural brain abnormalities seen in inbred Csf1r-/- mice, and they were viable as adults. Outbred E631Km/m mice lacked tissue-resident macrophages detected with a Csf1r-EGFP transgene or F4/80 in most major organs, including the brain, but aside from reproductive organs, which were underdeveloped, no gross histological abnormalities were observed. E631Km/m genotype was associated with reduced blood monocytes, the loss of circulating C1Q, reduced IGF1, and increased CSF1. In mice, F4/80+/CD169+ resident marrow macrophages are believed to be essential components of erythroblastic and hematopoietic island niches. These cells were undetectable in E631Km/m marrow. Their absence was associated with granulocytosis and B-cell deficiency in marrow, blood, and spleen, whereas the relative abundance of pluripotent and committed progenitors was not affected. Erythropoietic homeostasis was also maintained; erythroblasts were physically associated with a minor residual population of CSF1R-independent CD169-/F4/80+ marrow macrophages. We conclude that many developmental and homeostatic functions attributed to mouse resident-tissue macrophages are redundant, species-specific, or restricted to inbred strains.