The dual roles of uterine monocytes in regulation of tissue homeostasis throughout reproductive cycles in health and disease

Inflammation occurs during the recurring cycles of tissue degradation, repair and remodeling in the uterus, but the mechanisms by which the immune system contributes to uterine tissue integrity are unclear. We reveal that uterine monocytes have dual roles in both tissue remodeling and inflammation, depending on the reproductive cycle stage. Circulating inflammatory monocytes infiltrated the uterus before their differentiation into proinflammatory or pro-repair macrophages, depending on interferon-γ and transforming growth factor-β, respectively. Human monocyte numbers peaked before the window of implantation, when an inflammatory environment is required for embryo implantation. Uterine monocytes exhibited cytotoxic properties, regulating epithelial cell apoptosis. Bioinformatic analyses of receptor–ligand interactions indicated that monocytes dominated interactions between myeloid cells and fibroblasts. These pathways were disrupted in uterine fibrosis, marked by excess inflammatory monocytes or macrophages and a loss of rhythmicity through reproductive cycles. These data reveal a key role for monocytes and their progeny in the regulation of uterine tissue homeostasis.