IL-33 activates ILC2 expansion and modulates endometriosis

Abstract

Abstract Introduction: Chronic inflammation drives endometriosis (EM) and its associated symptoms. Interleukin (IL)-33, has gained therapeutic interest as it is elevated in the plasma, peritoneal fluid (PF), and lesions of EM patients. However, how IL-33 contributes to EM is largely unknown. For the first time, we demonstrate, using both human samples and murine models, that IL-33 expands local group 2 innate lymphoid cells (ILC2s) and that IL-33 activated ILC2s modulate hallmark features of EM. Methods: We identified ILC2s (CD45+Lin−CRTH2+CD127+ST2+) in the PF of EM patients using flow cytometry. Using immunofluorescence, we determine whether IL-33 forms epithelial or stromal cell niches within the EM lesion. Then, using our well established EM model, we induced EM in female C57Bl/6 mice and treated with PBS or IL-33. Hallmark features of EM were assessed including inflammation (using multiplex cytokine analysis), immune cell profiling (using flow cytometry), and lesion architecture (using immunohistochemistry and Nanostring transcriptomic profiling). To establish cause and effect, we treated ILC2 deficient mice with PBS (n=5) or IL-33 (n=5). Unpaired t-tests and one-way ANOVAs were done when appropriate. Results/Discussion: In humans, ILC2s are present and elevated in EM patients (n=5) compared to healthy donors (n=3) and IL-33 colocalized with both epithelial and stromal cells within the EM lesion. Using murine models, IL-33 drove hallmark features of EM including increased inflammation, alterations in PF immune cells (including eosinophils, T cells, macrophages and ILC2s), as well as increased lesion proliferation, neurogenesis and fibrosis. Using ILC2 deficient mice, we show that IL-33 induced pathology is ILC2 dependent.