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.