Coordinate regulation of tissue macrophage and dendritic cell population dynamics by CSF-1

Tissue macrophages (Mφs) and dendritic cells (DCs) play essential roles in tissue homeostasis and immunity. How these cells are maintained at their characteristic densities in different tissues has remained unclear. Aided by a novel flow cytometric technique for assessing relative rates of blood-borne precursor recruitment, we examined Mφ and DC population dynamics in the pregnant mouse uterus, where rapid tissue growth facilitated a dissection of underlying regulatory mechanisms. We demonstrate how Mφ dynamics, and thus Mφ tissue densities, are locally controlled by CSF-1, a pleiotropic growth factor whose in situ level of activity varied widely between uterine tissue layers. CSF-1 acted in part by inducing Mφ proliferation and in part by stimulating the extravasation of Ly6C(hi) monocytes (Mos) that served as Mφ precursors. Mo recruitment was dependent on the production of CCR2 chemokine receptor ligands by uterine Mφs in response to CSF-1. Unexpectedly, a parallel CSF-1-regulated, but CCR2-independent pathway influenced uterine DC tissue densities by controlling local pre-DC extravasation rates. Together, these data provide cellular and molecular insight into the regulation of Mφ tissue densities under noninflammatory conditions and reveal a central role for CSF-1 in the coordination of Mφ and DC homeostasis.