The Role of the Interleukin-33/Group 2 Innate Lymphoid Cell Axis in Endometriosis Pathophysiology
Year: 2026
Type: dissertation
Abstract: Endometriosis (EM) is a heterogenous, chronic inflammatory disease affecting approximately 200million women worldwide. Despite the staggering impact on patients and healthcare systems, the disease remains poorly diagnosed and ineffectively treated. EM is recognized as a multifactorial disease with significant involvement of dysfunctional immune responses contributing to lesion establishment and subsequent progression. This thesis addresses immune dynamics within the local EM lesion microenvironment to uncover features of tissue specific immune activation and targets for therapeutic intervention to alleviate the inflammatory burden of disease. We specifically identify tertiary lymphoid structures (TLSs)- organized immune cell aggregates present in chronically inflamed tissues- as features of the EM lesion. This finding emphasizes the coordinated inflammatory response in EM and raises fundamental questions as to TLS involvement in disease progression and pathophysiology. We next interrogated the interleukin-33/group 2 innate lymphoid cell (IL-33/ILC2) axis in both human patient samples and several conditional knockout mouse models of EM, to address how and whether the IL-33/ILC2 axis perpetuates EM pathophysiology. We identify significant enrichment of IL-33/ILC2 axis mRNA transcripts in EM lesions compared to control endometrium. Characterization of peritoneal fluid ILC2s from EM patients, demonstrated no change in cell abundance but indicated potential functional alterations across disease severity. Further, we uncover interactions between ILC2s and an immunomodulatory fibroblast subtype called mesenchymal stromal cells (MSCs), in a syngeneic mouse model of EM. Our data reveal that ILC2 expansion is significantly reduced in the presence of MSCs in vitro yet this interaction induces secretory and transcriptional alterations that support immune cell recruitment and an EM lesion maintenance phenotype. Finally, using a specific ILC2-deficient mouse model we provide conclusive evidence that ILC2s are required for IL-33-mediated inflammation and EM lesion remodeling. Targeting of this axis through neutralization of the IL-33 receptor (ST2), blunts the associated type 2 inflammatory response in a seemingly ILC2-dependent manner. Together, this work identifies ILC2s as critical regulators of IL-33-mediated type 2 inflammation and holds promise for novel immune based therapeutic targeting of the IL-33/ILC2 axis within EM.
Author: Zutautas, Katherine Briana
Language: English
Subfield: Reproductive Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7208087696