Harnessing the CD16-PI3Kγ axis in peritoneal CD14^hi macrophages: A transformative approach to endometriosis...

Endometriosis (EMS) is a prevalent estrogen-dependent gynecological disorder characterized by ectopic growth of endometrial tissue. Central to its pathophysiology, peritoneal CD14^hi macrophages exhibit a pro-EMS phenotype and drive disease progression. These macrophages originate from CD16^-CD14⁺ monocytes and co-express functional surface markers critical for EMS development. We demonstrate that endometrial stromal cells (ESCs) exert significantly stronger regulatory effects on CD14^hi macrophage polarization than estrogen alone. Crucially, CD16 maintains peritoneal CD14^hi macrophage homeostasis in ovarian EMS. To investigate CD16's role in vivo, we established a novel EMS mouse model (WH-EMS) by intraperitoneal grafting of wild-type uterine tissues into FcγRIII^-/- (CD16-deficient) female mice. Within this model, peritoneal FcγRIII^- macrophages exhibited impaired immunocompetence (diminished CD80 and IL4 expression), whereas macrophages infiltrating ectopic lesions displayed pronounced immune tolerance (elevated IL-4 expression). Pharmacologically targeting CD16 downstream signaling, PI3Kγ inhibition via IPI-549 attenuated ESC-induced differentiation of both CD14^hi and CD14^low macrophages in vitro, ultimately ameliorating pathological conditions in WH-EMS mice. This cumulative evidence indicates that CD14^hi macrophages promote EMS progression through CD16-dependent mechanisms. Consequently, therapeutic targeting of CD16 or its downstream effectors (e.g., PI3Kγ) represents a promising strategy for clinical EMS management.