TREM2 deficiency attenuates endometriosis progression by inhibiting M2 polarization of SpMs and suppressing SIRPα to enhance phagocytosis†.

Abstract

Endometriosis (EMS) is characterized by a disrupted peritoneal immune microenvironment where alternatively activated anti-inflammatory (M2) macrophage polarization and impaired phagocytosis promote lesion survival. Single-cell RNA-sequencing (ScRNA-seq) of the peritoneal macrophages from an EMS patient revealed elevated triggering receptor expressed on myeloid cells 2 (TREM2) and signal regulatory protein alpha (SIRPα). The expression of TREM2 and SIRPα is positively correlated, and each is positively correlated with estrogen response. A mouse EMS model was established by intraperitoneal injection of estrogen primed mouse endometrial fragments into recipient female mice. In vitro estrogen treatment of RAW 264.7 cells indicated increased TREM2/SIRPα expression and enhanced phagocytosis of lesion cells derived from wild-type (WT) EMS ectopic lesions. Peritoneal macrophages from mice with EMS were analyzed using flow cytometry for the expression of TREM2 and SIRPα. The assessment of F4/80, CD206, and SIRPα expressing cells within the lesions was performed through the implementation of multicolor immunohistochemistry (mIHC). Small peritoneal macrophages (SpMs, F4/80low CD11blow) were markedly increased in the EMS model. Trem2 knockout (KO) mice, as the recipient, showed smaller ectopic lesion size and less lesion formation. TREM2 deficiency inhibited SpM polarization into M2 and downregulated their SIRPα expression, while enhancing phagocytic activity. Mechanistically, estrogen pretreatment upregulated TREM2, which correlated with SIRPα upregulation and impaired phagocytosis. Under estrogen exposure, TREM2 knockdown RAW 264.7 cells potentiated phagocytosis. Thus, TREM2 is an important contributing pathogenic factor in promoting EMS by enhancing M2 polarization and suppressing phagocytosis via SIRPα upregulation. Our data suggest that blocking TREM2 may benefit EMS patient.