Understanding the role of IL-33 in endometriosis associated inflammation and pathology

Abstract Introduction Endometriosis (EM) is a chronic inflammatory disease categorized by the growth of endometrial tissue on the ovaries, peritoneal wall and other internal organs. Despite it’s prevalence (176 million women worldwide), the etiology is unknown. Currently, there is a significant knowledge gap regarding how the immune microenvironment contributes to the progression of EM (specifically inflammation, pain and fibrosis). We have shown that interleukin(IL)-33 is produced by EM lesions and drives pathology in a mouse model of EM. We are now investigating, mechanistically, how IL-33 contributes to EM and whether IL-33 neutralization could alleviate the pathology. Methods Female C57BL/6 mice were induced with EM and were treated with PBS (n=10) or IL-33 (n=10) every other day. After 2 weeks, the mice were euthanized and plasma, peritoneal fluid (PF) and EM lesions were collected. Cytokines in the plasma and PF were analyzed using a multiplex array. Immune cell populations in the PF were evaluated using CyTOF. Finally, sectioned lesions were stained for markers of innervation, proliferation and fibrosis. To establish cause and effect, mice were induced with EM and treated with IL-33+anti-IL-33 antibody (n=10) or IL-33+isotype control (n=10). Results Mice treated with IL-33 had elevated cytokines (e.g. IL-5) in the plasma and PF and EM lesions exhibited drastic changes in morphology. Additionally, both innate and adaptive immune cells were altered in the PF of IL- 33 treated mice. Neutralizing IL-33 reduced inflammation and immune cell recruitment. Conclusions Overall, these results show that IL-33 drives hallmark pathologies of endometriosis and neutralization of IL-33 could provide a novel therapeutic target for EM.