C/EBPβ deletion in macrophages impairs alveolar budding by altering the Wnt landscape during mammary gland development

Macrophages have important roles in mammary gland development and tissue homeostasis, but the specific mechanisms that regulate macrophage function need further elucidation. We have identified C/EBPβ as an important macrophage factor that is present in multiple populations of the normal mammary gland. Mammary glands from mice with C/EBPβ-deficient macrophages showed a significant decrease in alveolar budding during the estrus cycle. Deletion of C/EBPβ from macrophages resulted in changes in cytokine production, and an inability of both epithelial cells and macrophages to respond progesterone. RNA sequencing showed significant changes in PR-responsive genes and alterations in the Wnt landscape of epithelial cells in mammary glands that lacked C/EBPbeta in macrophages, which have been shown to mediate stem cell expansion during diestrus. These studies suggest that C/EBPbeta is a critical macrophage factor that facilitates macrophage-epithelial crosstalk during a key stage of mammary gland tissue homeostasis, and have critical implications for how disruption of tissue homeostasis can lead to tumorigenesis.