Interleukin‐22 secreted by ectopic endometrial stromal cells and natural killer cells promotes the recruitment of macrophages through promoting CCL2 secretion

Problem During endometriosis, there is an increase in the number of dysfunctional macrophages; however, the mechanisms underlying macrophage recruitment are not well understood. The aim of the present study was to determine the role of natural killer (NK) cell‐mediated secretion of chemokine (C‐C motif) ligand 2 (CCL2) from endometrial stromal cells (ESCs) in the recruitment of macrophages. Method of study Normal ESCs (nESC) and ectopic ESCs (eESCs) were separately co‐cultured with NK cells for a macrophage chemotaxis assay, and the number of chemotactic macrophages was counted. The expression of interleukin‐22 (IL‐22) and IL‐22 receptors was detected by ELISA and flow cytometry, respectively. eESCs were treated with 0.01, 0.1, and 1 ng/mL recombinant human IL‐22 (rhIL‐22) to determine the most effective concentration for stimulating CCL2 production. Following treatment with 1 ng/mL rhIL‐22, secretion of CCL2 was detected from both the eESC monoculture and the eESC/NK co‐culture. Results Compared with the eESC monoculture, the eESC/NK co‐culture recruited a significantly higher number of chemotactic macrophages. There was also an increase in the levels of IL‐22 and CCL2 secreted when eESCs were co‐cultured compared with the monoculture. Treatment with rhIL‐22 resulted in an increase in the levels of CCL2 secreted by eESCs, and the IL‐22‐induced CCL2 secretion was reversed by the IL‐22 antagonist, αIL‐22. Increased expression of IL‐22 resulted in an increase in the number of chemotactic macrophages, but was reversed by αIL‐22 and CCL2 antagonist (αCCL2). Conclusion Interleukin‐22 and CCL2 secretion by eESCs stimulated by NK cells contributes to the induction of macrophage recruitment and is thus implicated in the development of endometriosis.