Biology subjects

Broncano, A. V.

Publications and source records attributed to Broncano, A. V..

4 recordsLinked to original sources

bioRxiv2025

ERb limits T cell-mediated inflammation to maintain immune homeostasis

Many autoimmune diseases exhibit a female sex bias in prevalence and severity, yet the mechanisms for this remain unclear. 17{beta}-estradiol, a steroid sex hormone with established immunomodulatory roles, signals through the nuclear receptors ER and ER{beta}, which are expressed by CD4+ T cells. Expression of ER{beta} is reduced in CD4+ T cells isolated from autoimmune disease patients, suggesting that dysregulated E2 signaling contributes to inflammation. We previously identified a novel role for ER{beta} in promoting the TGF{beta}-dependent differentiation of Foxp3+ Tregs, supporting the idea that ER{beta} has anti-inflammatory functions. In this study, we investigated the functional role of ER{beta} in effector T cells, which drive pathogenesis of many autoimmune diseases. We found that CD4+ T cells isolated from mice globally deficient in ER{beta} exhibit enhanced proliferation and Th1 polarization ex vivo, together with elevated levels of proinflammatory cytokines in response to T cell receptor (TCR) stimulation. We also found that transfer of ER{beta}-KO T cells to immunodeficient mice results in significantly worse inflammation in a murine model of colitis. Together, these findings suggest that T cell-specific ER{beta} functions as a brake on T cell-mediated inflammation, thereby helping to maintain immune homeostasis. HighlightsO_LICD4+ T cells express the nuclear estrogen receptor ER{beta} C_LIO_LIER{beta}-deficient T cells express higher levels of inflammatory cytokines and are hyperproliferative ex vivo C_LIO_LIDeletion of ER{beta} increases T cell-mediated inflammation in a murine model of colitis C_LI CRediT authorship contribution statementSKM: investigation, formal analysis, visualization, writing - original draft; AVB: investigation, formal analysis, visualization, writing - original draft and review and editing; SMS: investigation and formal analysis; CMS: investigation and formal analysis, ADK: investigation, MLR: investigation, WBT: investigation; WAG: conceptualization, funding acquisition, project administration, resources, supervision, formal analysis, visualization, writing-review and editing.

immunology↗

bioRxiv2024

Sex differences in colonic inflammation are driven by epithelial-specific expression of estrogen receptor alpha

Background & AimsInflammatory bowel disease (IBD) patients exhibit altered expression of nuclear estrogen receptors alpha and beta (ER, ER{beta}) and G-protein coupled estrogen receptor 1 (GPER1). We previously showed that deletion of ER protects against intestinal damage selectively in female mice; however, the mechanisms conferring sex-specific protection are poorly understood. The goal of this study was to compare ER- and ER{beta}-specific mechanisms contributing to intestinal epithelial function in males and females. MethodsExpression of ER, ER{beta}, and GPER1 was evaluated in colonocytes from wild-type (WT) male and female mice. Intestinal epithelial cell (IEC)-specific ER and ER{beta} knockout mice were developed and challenged with dextran sulfate sodium (DSS). Colonic organoids were used to identify estrogen-dependent and -independent effects on cellular growth, differentiation, and transcriptional regulation in WT, ER-KO, and ER{beta}-KO IECs. ResultsColonic IECs showed significant expression of ER, ER{beta}, and GPER1 as well as Cyp19A1, which catalyzes production of 17{beta}-estradiol (estrogen). Female mice lacking ER specifically in colonic IECs showed protection from DSS-induced injury, whereas males showed increased pathology. Organoids derived from male ER-KO mice showed enhanced proliferation and decreased expression of key functional genes even without exogenous estrogen; however, colonoids derived from female ER-KO mice transcriptional analysis showed a protective gene signature. These findings reveal that deletion of ER differentially contributes to enhanced barrier function and resistance to inflammation in females, but to dysfunctional hyper-proliferation in males. ConclusionsER signaling within IECs drives opposing sex-dependent effects on the development, regenerative capacity, and inflammatory susceptibility of the intestinal epithelium.

cell biology↗

bioRxiv2022

Sex-specific niche signaling contributes to sexual dimorphism following stem cell transplantation

Hematopoietic stem cell (HSC) transplantation (HST) is a curative treatment for many hematopoietic cancers and bone marrow (BM) disorders but is currently limited by numerous complications including a lengthy recovery period, prolonged neutropenia resulting in severe infections and bleeding, and a high incidence of graft vs. host disease (GVHD). While clinical studies have demonstrated that sex mismatch, notably male recipients with female donor cells, results in increased risk of GVHD (likely due to male recipient minor histocompatibility antigens targeted by donor female T-cells 1), increased non-relapse mortality, and decreased overall survival, the mechanisms underlying sex-determinants on hematopoiesis and post-transplant recovery are not clear. In this manuscript we have identified: 1) unique expression of hematopoietic niche factors in the BM and spleens of male and female mice, 2) altered kinetics of hematopoietic reconstitution following transplantation when male vs. female BM is used as the donor cell source, 3) a sex-specific role for the recipient niche in promoting post HST recovery, and 4) a dose-dependent role for exogenous sex hormones in maintaining hematopoietic stem and progenitor cells (HSPCs). Taken together, these data demonstrate that sex-specific cellular and molecular signaling occurs during hematopoietic regeneration. Further identifying novel sex-dependent determinants of regeneration following transplantation will not only enhance understanding of steady state versus regeneration hematopoiesis but may also reveal unique (and potentially sex-specific) therapeutic targets to accelerate hematologic recovery. Key PointsO_LIMale and female mice display altered kinetics of regeneration following HST due to unique niche factors in hematopoietic compartments. C_LIO_LIExogenous steroid sex hormones uniquely regulate the pool of hematopoietic stem and progenitor cells and may impact transplantation outcomes. C_LI

immunology↗

bioRxiv2020

15-PGDH as a Negative Regulator of Age-Related Organ Fitness

Emerging evidence implicates the eicosanoid molecule prostaglandin E2 (PGE2) in conferring a regenerative phenotype to multiple organ systems following tissue injury. As aging is in part characterized by loss of tissue stem cells regenerative capacity, we tested the hypothesis that the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) contributes to the diminished organ fitness of aged mice. Here we demonstrate that genetic loss of 15-PGDH (Hpgd) confers a protective effect on aging of murine hematopoietic and gastrointestinal (GI) tissues. Aged mice lacking 15-PGDH display increased hematopoietic output as assessed by peripheral blood cell counts, bone marrow and splenic stem cell compartments, and accelerated post-transplantation recovery compared to their WT counterparts. Loss of Hpgd expression also resulted in enhanced GI fitness and reduced local inflammation in response to colitis. Together these results suggest that 15-PGDH negatively regulates aged tissue regeneration, and that 15-PGDH inhibition may be a viable therapeutic strategy to ameliorate age-associated loss of organ fitness. ARTICLE SUMMARY15-PGDH as a Driver of Age-Related Tissue Dysfunction

pathology↗