Biology subjects

Fattori, V.

Publications and source records attributed to Fattori, V..

5 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↗

bioRxiv2025

Adjuvant conditioning enhances neutrophil function while inducing a suppressive peritoneal macrophage phenotype

Adjuvants are widely used to boost the immune response during vaccination protocols. Our group has previously reported that repeated intraperitoneal administration of alum in mice, known as adjuvant conditioning (AC), creates an immunosuppressive environment that delays allogeneic graft rejection through NLRP3-dependent MDSC expansion. However, little is known about the effects of AC on the reprogramming of peritoneal cavity cells, particularly the different peritoneal macrophage populations and the effects in the adaptive immune response. We found a population-specific immune response to alum, with small peritoneal macrophages (SPMs) being more prone to inflammasome activation than large peritoneal macrophages (LPMs) in vitro. In vivo, alum exposure led to NLRP3-dependent macrophage disappearance reaction (MDR) of LPMs, which could be explained by aggregate formation and migration to the omentum. AC also induced the reprogramming of resident macrophages and infiltrating monocytes towards a less inflammatory state, making them more vulnerable to bacterial infections, but recruited neutrophils with enhanced killing ability. This suggests that AC may influence both innate and adaptive immunity in distinct ways, reprogramming cells to different profiles, indicating its potential as an immunosuppressive treatment for autoimmune diseases and transplant rejection.

immunology↗

bioRxiv2024

Adjuvant conditioning shapes the adaptive immune response and promotes trained immunotolerance via NLRP3/IL-1

Trained immunity enhances responsiveness of the innate immune system upon restimulation. Although adjuvants are used to enhance immune responses, we showed that repeated administration of alum, termed adjuvant conditioning (AC), establishes an immunosuppressive environment that delays allogeneic graft rejection by expanding myeloid-derived suppressor cells (MDSCs). Here, we show that AC-induced MDSCs suppress antigen specific adaptive responses both in vitro and in vivo, and that the immunosuppression is abolished in the absence of NLRP3 and IL-1 signaling. Allogeneic pancreatic islets transplanted into AC-treated NLRP3-/- mice are not protected, demonstrating that AC requires NLRP3 signaling. Finally, AC also has an immunosuppressive effect on human cells. Overall, our data show that AC establishes an immunosuppressive milieu via the NLRP3/IL-1 axis, leading to trained immunosuppression, or trained tolerance. Our findings give a potent mandate to explore the possibility to target the NLRP3/IL-1 pathway as a new promising strategy to condition transplant recipients and promote allograft tolerance.

immunology↗

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↗