Depletion and replacement of tissue-resident macrophages in mice with germ-line deletion of a conserved enhancer in the Csf1r locus

Expression of the Csf1r gene is regulated by a conserved enhancer, the fms-intronic regulatory element (FIRE). In mice with a germ-line deletion of FIRE (Fireko), CSF1R expression is undetectable in bone marrow progenitors and classical monocytes, but monocytopoiesis and non-classical monocyte maturation are unaffected. The loss of CSF1R is overcome in part by CSF2 in vitro and inflammatory recruitment in vivo. Fireko mice lack microglia and subpopulations of tissue-resident macrophages in peritoneum, kidney, heart, adipose, liver, skeletal muscle, pancreas, pituitary, adrenal and gonads. Heterozygous mutation impacts CSF1-induced proliferation and postnatal expansion of tissue macrophages. Physiological functions of the heart and kidney were not affected by the absence of macrophages. In a model of renal injury, macrophage recruitment and histopathology in wild-type and Fireko mice were indistinguishable, but there was a male-specific increase in serum creatinine and urea in the Fireko mice. Tissue-resident macrophages depleted in Fireko mice, including microglia, were replaced by donor-derived cells following intraperitoneal transfer of wild-type bone marrow at weaning. The Fireko mouse provides a platform to dissect functions of tissue-resident macrophages in development, homeostasis and pathology.