Biology subjects

Busada, J. T.

Publications and source records attributed to Busada, J. T..

7 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↗

bioRxiv2024

Chronic cigarette smoke exposure masks pathological features of Helicobacter pylori infection while promoting tumor initiation

Gastric cancer is the fifth most common cancer and the fifth leading cause of cancer deaths worldwide. Chronic infection by the bacterium Helicobacter pylori is the most prominent gastric cancer risk factor, but only 1-3% of infected individuals will develop gastric cancer. Cigarette smoking is another independent gastric cancer risk factor, and H. pylori-infected smokers are at a 2-11-fold increased risk of gastric cancer development, but the direct impacts of cigarette smoke on H. pylori pathogenesis remain unknown. In this study, male C57BL/6 mice were infected with H. pylori and began smoking within one week of infection. The mice were exposed to cigarette smoke (CS) five days/week for 8 weeks. CS exposure had no notable impact on gross gastric morphology or inflammatory status compared to filtered-air (FA) exposed controls in mock-infected mice. However, CS exposure significantly blunted H. pylori-induced gastric inflammatory responses, reducing gastric atrophy and pyloric metaplasia development. Despite blunting these classic pathological features of H. pylori infection, CS exposures increased DNA damage within the gastric epithelial cells and accelerated H. pylori-induced dysplasia onset in the INS-GAS gastric cancer model. These data suggest that cigarette smoking may clinically silence classic clinical symptoms of H. pylori infection but enhance the accumulation of mutations and accelerate gastric cancer initiation.

cancer biology↗

bioRxiv2024

Endogenous glucocorticoids are required for normal macrophage activation and gastric Helicobacter pylori immunity

Glucocorticoids are steroid hormones well-known for their potent anti-inflammatory effects. However, their immunomodulatory properties are multifaceted. Increasing evidence suggests that glucocorticoid signaling promotes effective immunity and that disruption of glucocorticoid signaling impairs immune function. In this study, we conditionally deleted the glucocorticoid receptor (GR) in the myeloid lineage using the LysM-Cre driver (myGRKO). We examined the impact on macrophage activation and gastric immune responses to Helicobacter pylori, the best-known risk factor of gastric cancer. Our results indicate that compared to WT, GRKO macrophages exhibited higher expression of proinflammatory genes in steroid-free conditions. However, when challenged in vivo, GRKO macrophages exhibited aberrant chromatin landscapes and impaired proinflammatory gene expression profiles. Moreover, gastric colonization with Helicobacter revealed impaired gastric immune responses and reduced T cell recruitment in myGRKO mice. As a result, myGRKO mice were protected from atrophic gastritis and pyloric metaplasia development. These results demonstrate a dual role for glucocorticoid signaling in preparing macrophages to respond to bacterial infection but limiting their pathogenic activation. In addition, our results support that macrophages are critical for gastric anti- Helicobacter immunity. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=159 SRC="FIGDIR/small/575574v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@7d5281org.highwire.dtl.DTLVardef@1b39ca2org.highwire.dtl.DTLVardef@f081caorg.highwire.dtl.DTLVardef@1d9215d_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2023

Comparison of gastric inflammation and metaplasia induced by Helicobacter pylori or Helicobacter felis colonization in mice

BackgroundGastric cancer is the fifth most diagnosed cancer in the world. Infection by the bacteria Helicobacter pylori (HP) is associated with approximately 75% of gastric cancer cases. HP infection induces chronic gastric inflammation, damaging the stomach and fostering carcinogenesis. Most mechanistic studies on Helicobacter-induced gastric cancer initiation are performed in mice and utilize either mouse-adapted strains of HP or the natural mouse pathogen Helicobacter felis (HF). Each of these infection models is associated with strengths and weaknesses. Here, we identified the differences in immunogenicity and gastric pathological changes associated with HP and HF infection in mice. Material and MethodsPMSS1 HP strain or with the CS1 HF strain were co-cultured with mouse peritoneal macrophages to assess their immunostimulatory effects. C57BL/6J mice were infected with HP or HF, and gastric inflammation, atrophy, and metaplasia development were assessed 2 months post-infection. ResultsHP and HF induced similar cytokine production from cultured mouse peritoneal macrophages. HP-infected mice caused modest inflammation within both the gastric corpus and antrum and did not induce significant atrophy within the gastric corpus. In contrast, HF induced significant inflammation throughout the gastric corpus and antrum. Moreover, HF infection was associated with significant atrophy of the chief and parietal cell compartments and induced expression of pyloric metaplasia markers. ConclusionsHP is poorly immunogenic compared to HF. HF induces dramatic CD4+ T cell activation, which is associated with increased gastric cancer risk in humans. Thus, HP studies in mice are better suited for studies on colonization, while HF is more strongly suited for pathogenesis and cancer initiation studies.

immunology↗

bioRxiv2021

Tristetraprolin prevents gastric metaplasia in mice by suppressing pathogenic inflammation

Aberrant immune activation is associated with numerous inflammatory and autoimmune diseases and contributes to cancer development and progression. Within the stomach, inflammation drives a well-established sequence from gastritis to metaplasia, eventually resulting in adenocarcinoma. Unfortunately, the processes that regulate gastric inflammation and prevent carcinogenesis remain unknown. Tristetraprolin (TTP) is an RNA-binding protein that promotes the turnover of numerous pro-inflammatory and oncogenic mRNAs. Here, we utilized a TTP-overexpressing model, the TTP{Delta}ARE mouse, to examine whether TTP can protect the stomach from adrenalectomy (ADX)-induced gastric inflammation and spasmolytic polypeptide-expressing metaplasia (SPEM). We found that TTP{Delta}ARE mice were completely protected from ADX-induced gastric inflammation and SPEM. RNA sequencing revealed that TTP overexpression suppressed the expression of genes associated with the innate immune response. Finally, we show that protection from gastric inflammation was only partially due to suppression of Tnf, a well-known TTP target. Our results demonstrate that TTP exerts broad anti-inflammatory effects in the stomach and suggest that therapies that increase TTP expression may be effective treatments of pro-neoplastic gastric inflammation.

immunology↗