Abstract
An increased number of highly active regulatory T cells (Tregs) and macrophages has been found in peritoneal fluid from women with endometriosis. Here, we show that the level of Tregs-derived soluble fibrinogen-like protein 2 (sFGL2) increases in the peritoneal fluid of women with endometriosis. Higher expression of FGL2 and its receptor CD32B is observed in eutopic endometrium and ectopic tissues. The production of sFGL2 in Tregs may be enhanced by several cytokines. sFGL2 selectively induces pro-repair macrophage polarization mainly through the activation of the SHP2-ERK1/2-STAT3 signaling pathway, and the suppression of the NF-κB signaling pathway. Furthermore, sFGL2 induces a much higher level of metallothionein (MT) expression that in turn facilitates pro-repair macrophages polarization. sFGL2-induced pro-repair macrophages promote Th2 and Tregs differentiation, creating a positive feedback loop. These findings suggest that sFGL2 secreted by Tregs skews macrophages toward a pro-repair phenotype via SHP2-ERK1/2-STAT3 signaling pathway, which is involved in the progression of endometriosis.
Highlights
An increased number of highly active regulatory T cells (Tregs) and macrophages has been found in peritoneal fluid from women with endometriosis
Fibrinogen-like protein 2 (FGL2) mediates its immunosuppressive activity by binding to inhibitory FcγRIIB (CD32B) receptors expressed by antigen presenting cells (APC), including dendritic cells (DC) and B cells, and soluble fibrinogen-like protein 2 (sFGL2) may inhibit the maturation of DC, resulting in the suppression of effector T cell responses and inducing apoptosis of B cells[17,18]
Higher levels of sFGL2 were detected in the peritoneal fluid of women with endometriosis compared to those without endometriosis, and sFGL2 levels were even higher in stage III–IV endometriosis (Fig. 1a)
Summary
An increased number of highly active regulatory T cells (Tregs) and macrophages has been found in peritoneal fluid from women with endometriosis. Soluble fibrinogen-like protein 2 (sFGL2) has been recently identified as a novel effector molecule of Tregs and plays a pivotal role in regulating both innate and adaptive immunity[10,11,12]. FGL2 has been found to be co-expressed with FOXP3 in cardiac and liver allograft models, implying its role in tolerant liver and heart allografts[16] These observations support the notion that sFGL2 serves as an effector molecule of Tregs. As an essential effector cell of innate immunity, macrophages play a crucial role in immune defense and in regulating inflammation, tissue repair, and remodeling[19,20] Macrophages and their activation states are characterized by plasticity and flexibility. The role of MT in contributing to modulate macrophage phenotype remains unclear
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