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 4

IL-33 alters EMS lesion proliferation, angiogenesis, innervation, and fibrosis.

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IL-33 alters EMS lesion proliferation, angiogenesis, innervation, and fi...
(A and B) Representative images of immunohistochemical staining using Ki67, a marker for proliferation, in PBS-treated (n = 5) and IL-33–treated (n = 5) mouse lesions. (C) Quantitative analysis of the percentage of positive area of Ki67+ cells. (D and E) Representative images of immunohistochemical staining using CD31, the marker for angiogenesis, in PBS- and IL-33–treated mouse lesions, respectively. (F) Analysis of the CD31+ area percentage in lesions from PBS- and IL-33–treated mice. (G) Unsupervised hierarchical clustering using Euclidean distance and complete linkage of angiogenesis-associated genes in RNA isolated from lesions of PBS- and IL-33–treated mice. (H and I) Representative images of immunohistochemical staining using the marker for innervation, Pgp9.5, in PBS- and IL-33–treated mouse lesions. (J) Analysis of the percentage of Pgp9.5+ area. The P value (P = 0.09) for this comparison is shown. (K and L) Representative images of Masson’s trichrome staining for collagen deposition in mouse lesions from PBS- and IL-33–treated groups. (M) Unsupervised hierarchical clustering using Euclidean distance and complete linkage of fibrosis-associated genes in RNA isolated from lesions of PBS- and IL-33–treated mice. Original magnification, ×200. Scale bar: 50 μm. *P < 0.05. Mean ± SD. Nonparametric Student’s t test with Mann-Whitney.