Implications of macrophage recruitment and activation in the immunopathophysiology of endometriosis

Endometriosis is an inflammatory gynaecological disease that affects 1 in 10 women globally. Characterized by the presence of endometrial-like tissues found proliferating outside the uterus, the disease is associated with chronic inflammation in the form of increased peritoneal cytokines and leukocyte populations, notably macrophages. Although several studies to date have highlighted the critical roles of macrophages in the progression of endometriosis and the promotion of peritoneal inflammation, the factors responsible for their recruitment and activation remained elusive. Through clinical observations, interleukin (IL)-33 was confirmed as to be a novel endometriosis-related damage-associated molecular pattern and herein we provided a characterization of its role in the regulation of macrophage activation and facilitation of lesion development in a mouse model of endometriosis. We provided evidence that IL-33, along with monocyte/macrophage-related chemotactic factor, monocyte chemoattractant protein-1 (MCP-1), were significantly increased within human endometriotic lesions compared to control endometrium. Evaluation of eutopic endometrium from women with endometriosis demonstrated macrophages were present in significantly greater abundance than control and may be central to promoting eutopic inflammation. Additionally, with emerging roles of the NLRP3 inflammasome in chronic inflammatory conditions, we sought to evaluate endometriosis patient peritoneal fluid and plasma by multiplex cytokine array and found aberrations in functional inflammasome products and regulators. Studies in our syngeneic, immunocompetent mouse model of endometriosis demonstrated that the administration of recombinant IL-33 induced significant lesion neovascularization and proliferation, as well as promoted robust peritoneal inflammation through the activation of macrophages. Furthermore, we found that inflammatory macrophage recruitment was regulated by the MCP-1/CCR2 signalling axis and was significantly attenuated by MCP-1 neutralization, which resulted in systemic and local perturbation in inflammation. These findings provided novel insights into the mechanisms regulating macrophage recruitment and activation which ultimately promoted endometriotic lesion development and inflammation in vivo.