Ovarian hormones-autophagy-immunity axis in menstruation and endometriosis

Abstract

Menstruation occurs in few species and involves a cyclic process of proliferation, breakdown and regeneration under the control of ovarian hormones. Knowledge of normal endometrial physiology, as it pertains to the regulation of menstruation, is essential to understand disorders of menstruation. Accumulating evidence indicates that autophagy in the endometrium, under the regulation of ovarian hormones, can result in the infiltration of immune cells, which plays an indispensable role in the endometrium shedding, tissue repair and prevention of infections during menstruation. In addition, abnormal autophagy levels, together with resulting dysregulated immune system function, are associated with the pathogenesis and progression of endometriosis. Considering its potential value of autophagy as a target for the treatment of menstrual-related and endometrium-related disorders, we review the activity and function of autophagy during menstrual cycles. The role of the estrogen/progesterone-autophagy-immunity axis in endometriosis are also discussed.

Keywords: NK cell; autophagy; endometrium; estrogen; macrophage; menstruation; neutrophil; progesterone.

Figure 1

The cyclical changes of ovarian steroid hormones, endometrium, and autophagy level in ESC and autophagy levels of ESC and the infiltration of immune cells during the menstrual cycle. First panel: Estrogen and progesterone levels throughout the menstrual cycle. Second panel: The morphological changes in the endometrium during the menstrual cycle. Third panel: Autophagy during the menstrual cycle. Bottom panel: Trafficking of Leukocytes into the endometrium during the menstrual cycle. The size of the cells represents the abundance. ESC: endometrial stromal cell.

Figure 2

Signal transduction mechanisms activated by ovarian steroid hormones on endometrial autophagy. Estrogen (E2) inhibits reactive oxygen species (ROS) production, which further suppresses autophagy in the endometrium. ROS has been shown to suppress the mTOR signaling pathway and further induce autophagy through several mechanisms, including activation of endoplasmic reticulum (ER) stress. Additionally, ER stress induces autophagy via the PI3K/AKT pathway and the COX-2/prostaglandins (PGs) axis. Of note, progesterone (P4) suppresses ER stress by restricting the PGF2α/ROS axis. However, the inhibition of mTOR signaling aggregates ER stress. Under stimulation from estrogen or progesterone, autophagy is induced through the activation of the MAPK/ERK pathway, which regulates autophagy-related genes through the transcription factor CREB. Therefore, the withdrawal of estrogen and progesterone leads to the inactivation of mTOR signaling and high levels of endometrial autophagy during menstrual phase through the HIF-1/ROS/AMPK signaling pathway, ER stress and MAPK/ERK signaling pathway.

Figure 3

The roles of ovarian steroid hormones-autophagy-immunity axis in menstruation. With the withdrawal of estrogen and progesterone, local inflammatory responses are initiated in the endometrium together with the activation of endometrial autophagy. Subsequently, MMPs are released and synergize with other inflammatory factors to participate in menstrual shedding. The release of a large number of chemokines (e.g., CXCL8, CXCL12, CCL2, CCL4 and CX3CL1) results in leukocyte infiltrations (neutrophils, uterine NK cell, macrophage, T cell, eosinophils, and mast cells) that can contribute to immune defense during menstruation. Residence of uterine NK cell (uNK) activated by endometrial autophagy and mast cells accelerate menstrual shedding by MMP9, Chymase, and etc. Additionally, elevated levels of COX-2 and PGs not only generate a hypoxic environment, but also induce autophagy in macrophages, neutrophils and mast cells that protect the endometrium from infections. COX-2 is also produced as a result of hypoxia during late menstruation, facilitating M2 macrophages polarization which participates in debris clearance, endometrial repair and remodeling. Meanwhile, uNK and neutrophils also contribute to endometrium repair and remodeling by secreting various cytokines (e.g, VEGF, FGF, and TGF-β). Neut: neutrophils; Mφ: macrophage; EOS: eosinophils; MC: mast cell.

Figure 4

The involvement of the ovarian steroid hormones-autophagy-immunity axis in the pathogenesis of endometriosis. In physiological situation, under the periodic regulation of estrogen and progesterone, autophagy levels in the endometrium also change in a CXCL12/CXCR4 dependent manner. During the menstrual period, the withdrawal of estrogen and progesterone leads to high levels of endometrial autophagy, contributing to endometrial exfoliation, immune defense, menstrual debris and endometrial fragment clearance by CD16⁺Granzyme B (Grzm)⁺INF-γ⁺ NK cells. In the presence of high concentrations of estrogen and progesterone resistance, however, autophagy-related genes (e.g., SNCA, RGS19, IGF1 ATGs, CXCR4, ESR1, and mTOR) are altered, leading to decreased endometrial autophagy. The suppression of endometrium autophagy directly accelerates the implantation, growth and angiogenesis of endometriotic lesions, whilst promoting the immune escape of endometriotic lesions through IL-8 and IL-23-mediated COX-2⁺CD16^-NK cell differentiation. IL-15 is also involved in this process. Additionally, IL-8 inhibits activated T cells, and COX-2-induced PGE2 release stimulates M2 macrophage differentiation, which can facilitate the immune escape, remodeling of ECM and neovascularization of endometriotic lesions. Therefore, the effects of aberrant ovarian steroid hormones-autophagy-immunity axis contribute to the occurrence and development of endometriosis.