J Leukoc Biol. 2026 Jun 10:qiag074. doi: 10.1093/jleuko/qiag074. Online ahead of print.
ABSTRACT
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 x 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 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 under-developed, 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-ve/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.
PMID:42266149 | DOI:10.1093/jleuko/qiag074