Harnessing the CD16-PI3Kγ axis in peritoneal CD14macrophages: A transformative approach to endometriosis management.

Abstract

Endometriosis (EMS) is a prevalent estrogen-dependent gynecological disorder characterized by ectopic growth of endometrial tissue. Central to its pathophysiology, peritoneal CD14macrophages exhibit a pro-EMS phenotype and drive disease progression. These macrophages originate from CD16CD14monocytes and co-express functional surface markers critical for EMS development. We demonstrate that endometrial stromal cells (ESCs) exert significantly stronger regulatory effects on CD14macrophage polarization than estrogen alone. Crucially, CD16 maintains peritoneal CD14macrophage 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 FcγRIIImacrophages 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 CD14and CD14macrophages in vitro, ultimately ameliorating pathological conditions in WH-EMS mice. This cumulative evidence indicates that CD14macrophages 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.