G-CSF and IL-6 may be involved in formation of endometriosis lesions by increasing the expression of angiogenic factors in neutrophils

Abstract

Evidence accumulated in recent years has revealed that neutrophils are involved in the initial establishment of endometriosis, which is well known as a chronic inflammatory disease. So far, why and how neutrophils promote the formation of early endometriosis are still unclear. In this study, using a mouse model of endometriosis, we demonstrated that endometriosis mice (EMs mice) had a significantly increased number of neutrophils in peritoneal fluids and lesions, and increased levels of granulocyte colony stimulating factor (G-CSF) and IL-6 in serum and peritoneal fluids compared to the control group. In the neutrophils and uterine fragments co-injection experiment, neutrophils regulated by G-CSF and IL-6 had a similar effect to neutrophils from EMs mice, increasing the number, area, weight and microvessel density of endometriotic lesions. Blocking the effect of G-CSF and IL-6 in EMs mice resulted in the number, area, and weight of endometriotic lesions to decrease. Depleting neutrophils in vivo by anti-Ly6G antibody, the microvessel density in the lesions of mice treated with neutrophils from EMs mice and neutrophils from pG/pI6 mice were significantly reduced. Neutrophils from EMs mice and neutrophils from pG/pI6 mice altered the expression levels of Mmp9, Bv8 and Trail genes compared to the neutrophils from PBS-treated mice. IL-6 cooperated with G-CSF induced a higher expression of phospho-STAT3 and STAT3 in neutrophils. These findings suggest that neutrophils modulated by G-CSF and IL-6 through the STAT3 pathway alter the expression levels of the angiogenesis related genes Mmp9, Bv8 and Trail, and may promote the establishment of early endometriosis.

Correlation Between Platelet-Lymphocyte Ratio and Neutrophil-Lymphocyte Ratio in Patients with Uterine Leiomyoma: A Cross-Sectional Study

“…Neutrophil activation enhances the recruitment of many different cell types involved in acute and chronic inflammation, thus activating pro-inflammatory effects [ 28 , 29 ]. A study in mice [ 30 ] showed a significant increase in the number of neutrophils and related cytokines in the peritoneal fluid of mouse models with endometriosis. For example, as one of the most common and inexpensive preoperative indicators, lymphocyte count is closely related to general health conditions and chronic inflammation [ 31 ].…”

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

“…GM-CSF, IL-10, and IL-17 [79]. G-CSF and IL-6 [78]. Decreased ---IL-8: interleukin-8; GM-CSF: granulocyte-macrophage colony-stimulating factor; G-CSF: granulocyte colony-stimulating factor; MIP-1β: macrophage inflammatory protein 1β; HNP1-3: human neutrophil peptides 1-3; IP-10: interferon-inducible protein 10; FGF-basic: basic fibroblast growth factor; IL-1ra: IL-1 receptor antagonist; EG-VEGF: endocrine gland-derived VEGF; GRO-α: chemokine growth-regulated-alpha.…”

“…In a syngeneic mouse model of endometriosis established through uterine horn peritoneal transplantation, neutrophils were significantly enriched at 24–72 hours of lesion establishment, with a peak at day 2–3 days, indicating that neutrophils may play a role in the early response of endometrial tissue to the local peritoneal environment [ 11 , 75 ]. In support of this, depletion of neutrophils with neutralizing antibodies to granulocyte receptor-1 (Gr-1) [ 76 ] or lymphocyte antigen 6 complex, locus G (Ly6G) [ 77 ] reduced the formation of endometriotic lesions in mice [ 11 , 76 , 78 ]. In the early stages of endometriotic lesion formation, neutrophils enhance lesion vascularization by increasing the production of local and systemic cytokines and angiogenic mediators [ 11 , 75 , 79 ].…”

“…In peritoneal fluid and ectopic endometrium of endometriosis model mice, neutrophil counts and levels of granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6) were significantly increased. G-CSF and IL-6 regulate neutrophils through STAT3 pathways and alter the expression of angiogenesis-related genes (Mmp9, Bv8, and Trail), which are involved in the establishment of early endometriosis [ 78 ]. Neovascularization is essential for the formation of endometriosis lesions, and inhibition of endometriosis angiogenesis with COX-2 inhibitors was shown to reduce neutrophil infiltration in endometriosis lesions [ 41 ].…”

Endometriosis-Associated Angiogenesis and Anti-angiogenic Therapy for Endometriosis

“…The immune system, particularly Interleukin (IL)-1β, the dominant interleukin-1 secreted by activated peritoneal macrophages, stimulates stromal cells to produce angiogenic molecules ( 14 ). Interleukin (IL)-6, produced by endometriotic stromal cells in the presence of (IL)-1β, also increases angiogenic factors in neutrophils to stimulate endometriosis-associated angiogenesis ( 17 , 23 ). IL-8, a pro-angiogenic factor, may potentiate neovascularization of ectopic implants, as elevation of IL-8 is observed in endometriosis patients ( 24 , 25 ).…”