Peritoneal immune microenvironment of endometriosis: Role and therapeutic perspectives

Abstract

Endometriosis, an estrogen-dependent chronic inflammatory disease characterized by the growth of endometrium-like tissues outside the uterine cavity, affects 10% of reproductive-age women. Although the pathogenesis of endometriosis is uncertain, it is widely accepted that retrograde menstruation results in ectopic endometrial tissue implantation. Given that not all women with retrograde menstruation develop endometriosis, immune factors have been hypothesized to affect the pathogenesis of endometriosis. In this review, we demonstrate that the peritoneal immune microenvironment, including innate immunity and adaptive immunity, plays a central role in the pathogenesis of endometriosis. Current evidence supports the fact that immune cells, such as macrophages, natural killer (NK) cells, dendritic cells (DCs), neutrophils, T cells, and B cells, as well as cytokines and inflammatory mediators, contribute to the vascularization and fibrogenesis of endometriotic lesions, accelerating the implantation and development of ectopic endometrial lesions. Endocrine system dysfunction influences the immune microenvironment through overexpressed estrogen and progesterone resistance. In light of the limitations of hormonal therapy, we describe the prospects for potential diagnostic biomarkers and nonhormonal therapy based on the regulation of the immune microenvironment. Further studies are warranted to explore the available diagnostic biomarkers and immunological therapeutic strategies for endometriosis.

Keywords: endometriosis; immune microenvironment; immunotherapy; macrophage; natural killer (NK) cells.

Figure 1

The immune microenvironment in the peritoneal cavity of the patient with endometriosis. Endometriotic lesions are comprised of epithelial cells, stromal cells, blood vessels, and nerve fibers that interact with immune cells, such as macrophages, natural killer cells, dendritic cells, neutrophils, B lymphocytes, and T lymphocytes, as well as a variety of cytokines, all of which contribute to the formation of the immune microenvironment. The role each component plays in the growth and development of endometriotic lesions is described here. NKG2D, NK Group 2, Member D; LILRB1/2, leukocyte immunoglobulin-like receptor B1/2; PD-1/PD-L1, programmed cell death protein 1/programmed cell death ligand 1; ESCs, endometrial stromal cells; IL, interleukin; HNP 1-3, human neutrophil peptides 1, 2, and 3; ENA-78, epithelial neutrophil-activating protein-78; VEGF, vascular endothelial growth factor; Th17 cells, T helper 17 cells; CTL, cytotoxic T lymphocytes; imDCs, immature dendritic cells; IFN-γ, interferon-γ; BCL6, B cell lymphoma 6.

Figure 2

The role macrophages play in the pathogenesis of endometriosis. The macrophages in the endometriotic lesions are composed of embryo-derived LpM and SpM, eutopic endometrial macrophages, and monocyte-derived LpM. Monocyte-derived macrophages were recruited into the peritoneal cavity and replenished the LpM pool. The decreased phagocytotic capacity of macrophages contributes to ESC survival and endometriotic tissue growth. Oxidative stress in macrophages triggers oxidative damage, tissue injury, and chronic inflammation. Macrophages promote angiogenesis and fibrosis through a variety of cytokines. Furthermore, the interaction between macrophages and nerves promotes the development of endometriosis. Additionally, overexpressed estrogen and progesterone resistance influence the function of macrophages. IL, interleukin; SpM, small peritoneal macrophages; LpM, large peritoneal macrophages; PGE2, prostaglandin E2; MMP, matrix metalloproteinase; SIRP-α, signal regulatory protein-α; RBC, red blood cell; ROS, reactive oxygen species; VEGF, vascular endothelial growth factor; FGF, fibroblast growth factor; TNF-α, tumor necrosis factor-α; LOXs, lysyl oxidases; TGF, transforming growth factor; NF-κB, nuclear factor kappa B; ESC, endometrial stromal cell; ECM, extracellular matrix; CSF, colony-stimulating factor; LIF, leukemia inhibitory factor; PAP-III, pancreatitis-associated protein III; IGF-1, insulin-like growth factor-1; BDNF, brain-derived neurotrophic factor; NT-3, neurotrophin-3; PGR, progesterone receptor; ER, estrogen receptor; COX-2, cyclo-oxygenase 2; HGF, hepatocyte growth factor.