IL-33 activates group 2 innate lymphoid cell expansion and modulates endometriosis
Jessica E. Miller, Harshavardhan Lingegowda, Lindsey K. Symons, Olga Bougie, Steven L. Young, Bruce A. Lessey, Madhuri Koti, Chandrakant Tayade
Jessica E. Miller, Harshavardhan Lingegowda, Lindsey K. Symons, Olga Bougie, Steven L. Young, Bruce A. Lessey, Madhuri Koti, Chandrakant Tayade
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Research Article Immunology Reproductive biology

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

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.

Authors

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

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Figure 3

IL-33 alters the localized, peritoneal immune profile in EMS murine model.

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IL-33 alters the localized, peritoneal immune profile in EMS murine mode...
(A, C, E, and I) Representative flow cytometric images and gating strategy for immune profiling conducted on PF samples, including eosinophils, Th cells, LPM, SPM, and ILC2s in PBS-treated (n = 5) and IL-33–treated (n = 5) WT mice. (A and B) Frequency of eosinophils (singlet, live, CD45+CD11b+F4/80+, Siglec-F+). (C and D) Frequency of Th cells (singlet, live, CD45+CD11b–, F4/80–, CD4+). (E and F) Frequency of LPM (singlet, live, CD45+CD11b+Siglec-F–F4/80hi, MHC-IIlo). (E and G) Frequency of SPM (singlet, live, CD45+CD11b+Siglec-F–F4/80lo, MHC-IIhi). (H) Unsupervised hierarchical clustering using Euclidean distance and complete linkage of M2 alternative activation–associated genes expressed in RNA isolated from lesions of PBS- and IL-33–treated mice (Nanostring nSolver). (I and J) Frequency of ILC2 (singlet, live, CD45+ lineage–CD25+Thy2+, ST2+). (K) Unsupervised hierarchical clustering using Euclidean distance and complete linkage of ILC2-associated genes expressed in total RNA isolated from lesions of PBS- and IL-33–treated mice. (L) Proportion of ST2+ cells in the PBS- and IL-33–treated mice. (M) Pie graphs depicting the range of PF cells that are ST2+ in the PBS- and IL-33–treated mice. *P< 0.05, **P < 0.01. Mean ± SD. Nonparametric Student’s t test with Mann-Whitney.