Pro-endometriosis macrophage release of IL-33 is key for endometriosis pain and lesion formation

Fattori, V.; S. Rasquel-Oliveira, F.; Ochoa, S.; Graf, E.; Bazzano, M. V.; Aung, T.; Vural, M.; Kohl, C.; Solano, M. E.; da Silva, M. D. V.; Heintz, O. K.; Brierley, S. M.; Verri, W. A.; Haerteis, S.; Castro, J.; Lawrenson, K.; Rogers, M. S.

doi:10.1101/2025.10.20.683510

bioRxiv · 10.1101/2025.10.20.683510

Pro-endometriosis macrophage release of IL-33 is key for endometriosis pain and lesion formation

Fattori, V.·S. Rasquel-Oliveira, F.·Ochoa, S.·Graf, E.·Bazzano, M. V.·Aung, T.·Vural, M.·Kohl, C.·Solano, M. E.·da Silva, M. D. V.·Heintz, O. K.·Brierley, S. M.·Verri, W. A.·Haerteis, S.·Castro, J.·Lawrenson, K.·Rogers, M. S.

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Abstract

Endometriosis is a painful gynecological inflammatory disease affecting up to 10% of females. When released by sensory neurons, calcitonin gene-related peptide (CGRP) shapes immunity, a process known as neuroimmune communication. We previously showed that nociceptor-derived CGRP polarizes macrophages into pro-endometriosis macrophages (PEMs) that mediates endometrial epithelial (endo-epi) cell proliferation and pain. However, the key mediators involved in this PEM-induced cell proliferation were unknown. Using unbiased approaches, we discovered that nociceptor-derived CGRP induces PEMs to produce IL-33. IL-33 binding to its receptor ST2 is key for endometriotic lesion growth and pain during endometriosis in mice as anti-IL-33 antibody treatment reduced evoked and spontaneous pain as well as lesion size. Chemical or genetic ablation of nociceptors or macrophages also resulted in lower levels of lesion IL-33, demonstrating a neuroimmune-driven mechanism for IL-33 production during endometriosis. In humans, we found that IL-33 is correlated with increased number of glands and fibrosis in lesions and that IL-33 expression in macrophages is also associated with genetic risk of endometriosis. We also provided evidence that suggests a dual role for IL-33 in endometriosis, in which, it is initially required for lesion formation and later for lesion maintenance only, and associated pain. Therefore, targeting IL-33/ST2 signaling may effectively treat endometriosis pain.

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Fattori, V., S. Rasquel-Oliveira, F., Ochoa, S., Graf, E., Bazzano, M. V., Aung, T., Vural, M., Kohl, C., Solano, M. E., da Silva, M. D. V., Heintz, O. K., Brierley, S. M., Verri, W. A., Haerteis, S., Castro, J., Lawrenson, K., Rogers, M. S.. 2025-10-21. Pro-endometriosis macrophage release of IL-33 is key for endometriosis pain and lesion formation. https://doi.org/10.1101/2025.10.20.683510

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