Biology subjects

Heintz, O. K.

Publications and source records attributed to Heintz, O. K..

3 recordsLinked to original sources

bioRxiv2025

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

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.

neuroscience↗

bioRxiv2023

Targeting NGF but not VEGF or BDNF signaling reduces endometriosis-associated pain in mice

IntroductionEndometriosis is a chronic inflammatory disease that affects [~]10% of women. A significant fraction of patients experience limited or no efficacy with current therapies. Tissue adjacent to endometriosis lesions often exhibits increased neurite and vascular density, suggesting that disease pathology involves neurotrophic activity and angiogenesis. ObjectivesWe aim to evaluate the potential for key tyrosine-kinase-receptor-coupled neurotrophic molecules to contribute to endometriosis-associated pain in mice. MethodsThe levels of VEGFR1 regulators (VEGFA, VEGFB, PLGF, and sVEGFR1) were quantified by ELISA in peritoneal fluid from endometriosis patients undergoing surgery and used to calculate VEGFR1 occupancy. We used genetic depletion, neutralizing antibody, and pharmacological approaches to specifically block ligand (NGF or BDNF) or neurotrophic receptor (VEGFR1, TRKs) in a murine model of endometriosis-associated pain. Endometriosis-associated pain was determined using the von Frey filaments method, quantification of spontaneous abdominal pain-related behavior, and thermal discomfort. Diseases parameters were evaluated by lesion size and prevalence. ResultsWe found that entrectinib (pan-Trk inhibitor) or anti-NGF treatments reduced evoked pain, spontaneous pain, and thermal discomfort. In contrast, even though receptor occupancy revealing that VEGFR1 agonist levels are sufficient to support pain, blocking VEGFR1 signaling via antibody or tamoxifen-induced knockout did not reduce pain or lesion size in mice. Targeting BDNF-TrkB with an anti-BDNF antibody also proved ineffective. ConclusionsThis suggests NGF-TrkA signaling, but not BDNF-TrkB or VEGF-VEGFR1, mediates endometriosis-associated pain. Moreover, entrectinib blocks endometriosis-associated pain and reduces lesion sizes. Our results also indicated that entrectinib-like molecules are promising candidates for endometriosis treatment. Credit author statementConceptualization: T.H. Zaninelli, V. Fattori, and M.S. Rogers; investigation and data curation: T.H. Zaninelli, V. Fattori, O.K. Heintz, K.R. Wright; A.C. Andrello, W.A. Verri Jr, M.S. Rogers; funding acquisition: M.S. Rogers,, S.A. Missmer, R.M. Anchan; methodology: T.H. Zaninelli, V. Fattori, and M.S. Rogers; human sample collection: S.A. Missmer, A.F. Vitonis, K.L. Terry, R.M. Anchan; animal breading and VEGFR1 ablation: D. Sim and H. Bukhari; resources: A.C. Andrello; D. Bree, T. Zheng, J. Wagner, W.A. Verri Jr, and M.S. Rogers; project administration: T.H. Zaninelli; supervision: V. Fattori, W.A. Verri Jr, and M.S. Rogers; visualization: T.H. Zaninelli, V. Fattori, W.A. Verri Jr, and M.S. Rogers; writing-original draft: T.H. Zaninelli; writing - editing and reviewing: all authors. All authors have read and approved the final version of the manuscript.

pharmacology and toxicology↗

bioRxiv2023

Nociceptor to macrophage communication through CGRP/RAMP1 signaling drives endometriosis-associated pain and lesion growth

Endometriosis is a debilitating and painful gynecological inflammatory disease affecting approximately 15% of women. Current treatments are ineffective for a significant fraction of patients, underscoring the need for new medical therapies with long-term benefits. Given the genetic correlation between migraines and endometriosis, we sought evidence for the role of CGRP-mediated neuroimmune communication in endometriosis. We found that mouse and human endometriosis lesions contained CGRP and RAMP1. In mice, nociceptor ablation reduced pain, monocyte recruitment, and lesion size, suggesting that nociceptors support endometriosis lesions. In vitro, CGRP-treated macrophages showed impaired efferocytosis and supported endometrial cell growth in a RAMP1-dependent manner. Treatment with FDA-approved drugs that block CGRP-RAMP1 signaling reduced evoked and spontaneous pain, and lesion size. Since the lack of drug efficacy at reducing ongoing pain drives most endometriosis therapy failure, our data demonstrating effectiveness of non-hormonal and non-opioid CGRP/RAMP1 blocking therapies may lead to clinical benefit for endometriosis patients.

neuroscience↗