Biology subjects

Pascoe, J. L.

Publications and source records attributed to Pascoe, J. L..

3 recordsLinked to original sources

bioRxiv2025

Endogenous glucocorticoids moderate the gastric inflammatory response to Helicobacter infection and protect from autoimmunity.

Background and AimsImmune responses to infection must balance pathogen clearance with minimizing tissue damage and autoimmunity. Chronic gastric inflammation caused by H. pylori damages the gastric mucosa and promotes carcinogenesis. Glucocorticoids are immunoregulatory hormones that limit immune activation in the stomach. This study aimed to determine how endogenous glucocorticoids regulate the gastric immune response to Helicobacter infection and their impact on preneoplastic lesion development. MethodsWe examined the role of endogenous glucocorticoids in shaping the gastric immune response to Helicobacter felis colonization. Gastric immune cell infiltration, atrophy, metaplasia, and preneoplastic lesion development were evaluated in adrenal-intact control mice and adrenalectomized (ADX) mice. Auto-reactive IgG antibodies were assessed using a mouse self-antigen array and by measuring their binding to healthy gastric tissue. ResultsLoss of endogenous glucocorticoids led to significantly increased H. felis-induced gastric T cell infiltration and proinflammatory cytokine expression compared to intact-infected controls. While all intact mice maintained chronic infection for up to 12 months, nearly all ADX mice eradicated H. felis within 2-3 weeks. Despite bacterial clearance, ADX mice continued to exhibit chronic gastric inflammation and developed dysplasia. Autoantibody profiling showed that both intact and ADX groups generated self-reactive IgG during active infection. However, only ADX mice sustained autoantibody production following bacterial eradication. ConclusionsEndogenous glucocorticoids attenuate gastric inflammation during Helicobacter infection, supporting bacterial persistence while maintaining immune tolerance. These findings suggest that heightened immune responses to H. pylori may trigger autoimmune gastritis (AIG) development, which can persist after H. pylori clearance and continue to drive gastric cancer risk.

immunology↗

bioRxiv2025

Androgen Signaling in Type 2 Innate Lymphoid Cells Drives Sex Differences in Helicobacter-Induced Gastric Inflammation and Atrophy

Background & AimsGastric cancer is the fifth most common cancer worldwide. Men are disproportionately affected by gastric cancer, which ranks as the fourth most common cancer in men compared to eighth in women worldwide. Chronic inflammation driven by Helicobacter pylori infection remains the leading gastric cancer risk factor. Emerging evidence suggests that sex hormones modulate immune responses, contributing to sex differences in infection outcomes and cancer susceptibility. This study investigates how androgens influence the gastric inflammatory response to Helicobacter infection and contribute to sex disparities in disease progression. MethodsMale and female C57BL/6 mice were colonized with Helicobacter felis to investigate sex differences in gastric inflammation. Androgen levels were manipulated by bilateral castration in males and dihydrotestosterone (DHT) treatment in females. Single-cell RNA sequencing was used to identify androgen-responsive leukocyte populations and to establish cell communication networks between leukocyte clusters. The functional roles of these cells were further defined using ILC2- and T cell-deficient mouse models. ResultsInfected female mice developed significantly more severe gastric inflammation, atrophy, and metaplasia infection compared to males. Androgen depletion by castration increased gastric inflammation and accelerated preneoplastic lesion development, while these pathological features were reduced by DHT treatment. Androgen-responsive type 2 innate lymphoid cells (ILC2s) were key initiators of gastric inflammation and ILC2 depletion abolished the sex differences in H. felis pathogenesis. ConclusionsThis study reveals that androgens suppress Helicobacter-induced gastric inflammation by modulating ILC2 activation. We found that androgens are protective, as androgen depletion exacerbated gastric inflammation and accelerated preneoplastic lesion development. These findings provide mechanistic insight into the age-related increase in male gastric cancer incidence, coinciding with declining androgen levels. Our results suggest that circulating androgen concentrations may serve as a prognostic biomarker for gastric cancer risk in men. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=120 HEIGHT=200 SRC="FIGDIR/small/643321v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@6cf3c3org.highwire.dtl.DTLVardef@f797d6org.highwire.dtl.DTLVardef@1118c21org.highwire.dtl.DTLVardef@106e2ab_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

In vitro to in vivo evidence for chemical disruption of glucocorticoid receptor signaling

Glucocorticoids are steroid hormones that regulate stress homeostasis, metabolism, and inflammatory responses. Dysregulation of the glucocorticoid receptor (GR) is linked to diseases such as obesity, mood disorders, and immune dysfunction. Endocrine-disrupting chemicals (EDCs) are widespread environmental contaminants known to interfere with hormone signaling, but their impact on glucocorticoid signaling remains unclear. While several GR-disrupting compounds have been identified in vitro, their in vivo effects remain largely unknown. In this study, we identified the agricultural agents dichlorodiphenyltrichloroethane (DDT) and ziram as GR-disruptors in vitro. In vivo, corticosterone co-treatment with DDT or the GR antagonist RU-486 inhibited the expression of classic GR-regulated transcripts in the liver. Furthermore, chronic exposure to DDT or RU-486 significantly reduced circulating B and T lymphocyte populations, respectively. These findings underscore the need to translate in vitro discoveries into in vivo models to assess the clinical relevance of GR-disrupting compounds. Moreover, they highlight the potential for xenobiotic-induced GR disruption to impair metabolic and immune homeostasis, potentially increasing disease susceptibility.

pharmacology and toxicology↗