The Abundance and Function of Neutrophils in the Endometriosis Systemic and Pelvic Microenvironment

Abstract

Endometriosis is a common inflammatory illness in which endometrial tissue grows outside the uterine cavity. Immune dysfunction is now widely acknowledged as the primary cause of endometriosis. The immune cell population represented by neutrophils is thought to play an essential role in the etiology, pathophysiology, and associated clinical outcome. There is growing evidence that neutrophils have a role in chronic and aseptic inflammatory diseases, and endometriosis patients have increased levels of neutrophils in plasma, peritoneal fluid, and ectopic endometrium. Here, we sought to review the function of neutrophils in the pathogenesis of endometriosis, with an emphasis on the role of neutrophils in regulating endometrial angiogenesis and the local inflammatory microenvironment.

Figure 1

Inflammatory events in menstruation. (a) Ovarian-derived estradiol and progesterone play a significant role in the structure and shape of the endometrium throughout the menstrual cycle. (b) Progesterone withdrawal leads to the release of chemokines into the surrounding tissues and the recruitment of neutrophils into the endometrium. Macrophages may have a proinflammatory (M1) phenotype in the early stages, and their phagocytic clearance of apoptotic cells is required to reduce local inflammation. Eosinophils are also recruited, while local mast cells become highly active and uterine natural killer (uNK) cells proliferate and release cytolytic chemicals. As these cells undergo a phenotypic shift, MMPs and degradative enzymes are released, stimulating the MMP activation cascade and driving ECM breakdown and endometrial rupture. (c) After menstruation, macrophages remove cellular debris while neutrophils of different phenotypes assist in the remodeling and repair of the functional endometrial layer.

Figure 2

The function of immune cells in the microenvironment of endometriotic lesions. During menstruation, according the theory of retrograde menstruation, live endometrial debris first returns to the peritoneal cavity, containing a large number of neutrophils, cytokines (IL-8), and angiogenic factors (VEGF and ANGPT1/2), which interact with various infiltrative immune cell populations and promote endometrial cell adhesion and cell proliferation. Under the influence of systemic and local abdominal immune dysfunction, immune cells and immune mediators promote the establishment and survival of lesions. The table above outlines the role of each immune cell type in the pathophysiology of endometriosis.

Figure 3

Mechanisms of neutrophil-mediated pathophysiology of endometriosis. The number of neutrophils increases significantly in the premenstrual period and participates in the shedding and repair of the endometrium. Endometriosis eutopic endometrium has a high neutrophil count, which overexpresses VEGF, IL-8, and ANGPT1/2, resulting in dysregulation of angiogenic activity and further tissue shedding to form ectopic endometrial lesions, shaping the inflammatory peritoneal microenvironment. A vicious cycle of recruiting neutrophils, secreting cytokines and growth factors, and promoting apoptosis of cytotoxic T cells is further formed. In this process, the increase of neutrophils in the circulating blood is accompanied by the weakening of phagocytosis, and pathophysiological pathways like NETs are also involved, generating a highly complex and dynamic microenvironment. IFN-γ: interferon-γ; VEGF: vascular endothelial growth factor; IL-17: interleukin-17; IL-8: interleukin-8; ANGPT1/2: angiopoietin 1 and 2; ENA-78: epithelial neutrophil activating peptide-78; CXCL10: interferon-gamma-induced protein-10; GRO-α: chemokine growth-regulated-alpha.