Macrophages originated IL33/ST2 inhibits ferroptosis in endometriosis via the ATF3/SLC7A11 axis

Abstract

Abstract Endometriosis is a gynecological inflammatory disease which linked with immune cells, specifically macrophages. And IL-33 secreted from macrophages is known to accelerate the progression of endometriosis. The periodic and repeated bleeding in endometriosis leads to a microenvironment with an excess of iron that is conducive to ferroptosis, a process related to intracellular ROS production, lipid peroxidation and mitochondrial damage. Hence, it is suggested that eESCs may have specific mechanisms to inhibit ferroptosis. However, it is currently unclear whether IL-33 directly regulates ferroptosis to influence the disease course in endometriosis. In this study, eESCs co-cultured with macrophages or stimulated with IL-33/ST2 were observed increased cell viability and migration. Additionally, IL-33/ST2 lessened intracellular iron and lipid peroxidation in eESCs exposed to erastin treatment. Furthermore, IL-33/ST2 treatment resulted in a notable elevation of SLC7A11 expression in eESCs due to its negative transcription factor ATF3 down-regulation, thereby suppressing ferroptosis. The P38/JNK pathway activated by IL-33/ST2 was also found to inhibit transcription factor ATF3. Therefore, we concluded that IL-33/ST2 constrains ATF3's role in suppressing SLC7A11 transcription via the P38/JNK pathway. The findings reveal that macrophage-derived IL-33 induces an upregulation of SLC7A11 in eESCs through the p38/JNK/ATF3 pathway, ultimately resulting in protection against ferroptosis in endometriosis. Moreover, we conducted an experiment in mouse endometriosis models that showed that a combination of IL-33-Ab and erastin treatment alleviated the disease, showing the promise of combining immunotherapy and ferroptosis therapy.