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

Abstract

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.