IL-33 activates group 2 innate lymphoid cell expansion and modulates endometriosis.

Jessica E Miller,Harshavardhan Lingegowda,Chandrakant Tayade,Bruce A Lessey,Madhuri Koti,Steven L Young,Lindsey K Symons,Olga Bougie

doi:10.1172/jci.insight.149699

Abstract

Chronic inflammation and localized alterations in immune cell function are suspected to contribute to the progression of endometriosis and its associated symptoms. In particular, the alarmin IL-33 is elevated in the plasma, peritoneal fluid, and endometriotic lesions from patients with endometriosis; however, the exact role of IL-33 in the pathophysiology of endometriosis is not well understood. In this study, we demonstrate, in both humans and a murine model, that IL-33 contributes to the expansion of group 2 innate lymphoid cells (ILC2s), and this IL-33–induced ILC2 expansion modulates the endometriosis lesion microenvironment. Importantly, we show that IL-33 drives hallmarks of severe endometriosis, including elevated inflammation, lesion proliferation, and fibrosis, and that this IL-33–induced aggravation is mediated by ILC2s. Finally, we demonstrate the functionality of IL-33 neutralization as a promising and potentially novel therapeutic avenue for treating the debilitating symptoms of endometriosis.

Highlights

176 million women worldwide suffer from endometriosis
We used human endometriosis patient samples to understand the spatial arrangement of IL-33 in the endometriotic lesion and for the first time, we identify the presence of ILC2s in the peritoneal fluid (PF) of human endometriosis patients
Using two different methodologies RAG2-/- treated with an anti-CD90.2 antibody (ILC2 depleted) and RAG2-/-IL-2rγ-/- (ILC2 deficient) mice, we show that the IL-33 driven inflammation, immune cell recruitment, lesion proliferation, and fibrosis are dependent on ILC2s

Summary

Introduction

176 million women worldwide suffer from endometriosis. Together with the emerging associative risk of developing ovarian cancer[1] and the enormous economic burden[2, 3], endometriosis is a critical public health concern that is conspicuously understudied. The widely accepted Sampson’s theory of pathogenesis suggests that during menstruation, shed endometrial fragments are refluxed into the peritoneal cavity where they evade immune surveillance and adhere to pelvic structures[4]. These fragments develop into endometrial-like lesions and subsequently exhibit chronic inflammation, undergo neuro-angiogenesis, and become highly fibrotic[5]. In endometriosis patients, the endometrium exhibits vast immune alterations and endometriotic lesions exhibit even greater immune deviations. The two most predominant symptoms of endometriosis, chronic pelvic pain and infertility, are often connected to aberrant inflammation[12, 13]. The precise mechanisms that underpin how inflammation contributes to chronic pelvic pain and infertility is not well understood

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Conclusion