Regulatory T cells induce polarization of pro-repair macrophages by secreting sFGL2 into the endometriotic milieu.

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.