MDSC Polarization and Helicobacter-induced Gastric Metaplasia

MDSC 极化和螺杆菌诱导的胃化生

• 批准号: 10687293
• 负责人: JUANITA L. MERCHANT
• 金额: $ 40.97万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10687293
• 关键词: 3' Untranslated Regions; Acute; Address; African American population; Alleles; Appearance; Atrophic; Bacteria; Bacterial Infections; Binding; Binding Sites; Cell Death; Cells; Chronic; DNA; Dendritic Cells; Elements; Endothelium; Epithelial; Epithelial Cells; Exhibits; Funding; Gastric Adenocarcinoma; Gastric Metaplasia; Genes; Genetic Transcription; Genome; Goals; Goblet Cells; HMGB1 gene; Helicobacter; Helicobacter Infections; Helicobacter pylori; Hispanic Americans; Histologic; Human; Immune; Immune response; Immunosuppressive Agents; Individual; Infection; Inflammation; Inflammatory Response; Injections; Interferon Type I; Interferon-alpha; Interferons; Interleukin-1 alpha; Intestines; Ligands; Link; Mesenchymal; Messenger RNA; Metaplasia; MicroRNAs; Minor; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Mucous body substance; Mus; Myeloid Cells; Myeloid-derived suppressor cells; Necrosis; Not Hispanic or Latino; Oncogenic; Organism; Organoids; Orthologous Gene; PTEN gene; Pathway interactions; Pattern; Pattern recognition receptor; Peptic Ulcer; Play; Population; Predisposition; Preneoplastic Change; Production; Proteins; Reporting; Role; Shapes; Signal Transduction; Signal Transduction Pathway; Stomach; Suppressor-Effector T-Lymphocytes; TLR9 gene; TNF gene; Testing; Tissues; Ubiquitination; Virulence Factors; Virus; Virus Diseases; acute infection; cytokine; gastric intestinal metaplasia; gastric tumorigenesis; gene product; granulocyte; injured; knock-down; malignant stomach neoplasm; mouse model; pathogen; phosphodiesterase V; polarized cell; programs; promoter; recruit; relating to nervous system; response; small molecule; smoothened signaling pathway; spasmolytic polypeptide; transcription factor; transcriptome sequencing; tumor; tumor growth; tumor-immune system interactions; ubiquitin isopeptidase

Metaplastic changes in the stomach typically develop when the gastric epithelium responds to chronic inflammation induced by such organisms as Helicobacter pylori (H. pylori). We previously showed that a subset of interferon (IFN)-regulated myeloid cells express Schlafen4 (Slfn4), a direct target of the Gli1 transcription factor and exhibit T cell suppressor function indicative of myeloid-derived suppressor cells (MDSCs). These granulocytic myeloid-derived suppressor cell subset (Gr-MDSCs) contribute to the emergence of gastric intestinal metaplasia and spasmolytic-polypeptide-expressing metaplasia (SPEM). We propose that debris from damaged gastric epithelia and immune cells as well as dying bacteria induce a signal transduction pathway generate pathogen recognition ligands collectively known as damage-activated molecular patterns or DAMPs. Type 1 interferons (IFNs) are typically induced by DAMP ligands, e.g., HMGB1, mitochondrial and unmethylated CpG DNA. We have recently found that a SNP within the human TLR9 promoter correlates with atrophy, IM, and GAC. Moreover, the TLR9 SNP creates an NFB binding site resulting in higher TLR9 expression. H. pylori infection sensed by both plasmacytoid dendritic cells (pDC) and gastric epithelial cells (GEC) induces TLR9 expression and ultimately secrete type 1 IFNs (IFNα/β). Thus, in addition to host signaling from injection of the H. pylori virulence factor CagA, H. pylori remnants and cell debris are capable of initiating an immune suppressor response. Since we previously showed that the presence of these Slfn4+- MDSCs correlates with early pre-neoplastic changes, we hypothesize that crosstalk between a subset of immune suppressor cells (SLFN+-MDSCs) and gastric epithelial cells stimulate feedforward signals that ultimately re-program the epithelium towards metaplasia, before the appearance of gastric cancer. Hedgehog signaling (Gli1) and IFNα synergistically induce Slfn4+/SLFN12L+-MDSCs. Three Specific aims are proposed: In Aim 1, we will determine the impact of DAMP ligands (H. pylori DNA) on IFN-producing pDCs versus gastric epithelial cells. In Aim 2, we will demonstrate how Schlafens protect a subset of MDSCs from self- destruction by IFN-induced ROS. In Aim 3, we will demonstrate how PDE inhibition blocks Slfn4/SLFN12L+- MDSCs and modulates the immune microenvironment in an autochthonous model of gastric tumorigenesis. A combination of mouse models and human organoids will be used to understand the role of DAMP ligands in shaping the immune microenvironment after chronic inflammation has occurred. Conditional deletion of Slfn4 and knockdown of the human ortholog SLFN12L will be used to dissect how these Schlafens protect the IFN- responsive MDSCs from cell death. Finally, since modulating the immune microenvironment plays a significant role in tumor growth, we will examine whether small molecules that disrupt or eliminate these Slfn4/SLFN12L impact tumor growth. Completion of these aims will result in a better understanding of the how this important subset of immune modulatory cells are induced, maintained and ultimately targeted by small molecules.

当胃上皮对慢性反应时，陡峭的变化通常会出现 由幽门螺杆菌（H. Pylori）等生物引起的炎症。我们以前证明了一个子集 干扰素（IFN）调节的髓样细胞表达schlafen4（SLFN4），这是GLI1转录的直接靶标 因子和暴露的T细胞抑制器功能指示髓样衍生的抑制细胞（MDSC）。这些 粒细胞髓样衍生的抑制细胞子群（GR-MDSC）有助于胃的出现 肠化生和痉挛性 - 溶霉菌表达化生（SPEM）。我们提出了碎片 来自受损的胃皮细胞和免疫细胞以及垂死的细菌诱导信号转导 途径产生病原体识别配体统称为损伤激活的分子模式或 潮湿。通常由湿配体诱导1型干扰素（IFN），例如HMGB1，线粒体和 未甲基化的CpG DNA。我们最近发现，人类TLR9启动子中的SNP与 萎缩，IM和GAC。此外，TLR9 SNP创建一个NFB结合位点，导致更高的TLR9 表达。幽门螺杆菌树突状细胞（PDC）和胃皮细胞都感染了幽门螺杆菌感染 （GEC）诱导TLR9表达，并最终分泌1型IFNS（IFNα/β）。除了主持人 幽门螺杆菌病毒因子CAGA，幽门螺杆菌残留物和细胞碎屑的信号传导能够 启动免疫抑制器反应。由于我们先前表明了这些slfn4+ - 的存在 MDSC与早期的前塑性变化相关，我们假设该子集之间的串扰 免疫抑制细胞（SLFN+-MDSC）和胃皮细胞刺激前馈信号 最终在胃癌出现之前重新编程了上皮的上皮。刺猬 信号传导（GLI1）和IFNα协同诱导SLFN4+/SLFN12L+-MDSCS。提出了三个具体目标： 在AIM 1中，我们将确定潮湿配体（H. Pylori DNA）对产生IFN的PDC的影响 胃上皮细胞。在AIM 2中，我们将展示Schlapens如何保护MDSC的子集免受自我的侵害 IFN诱导的ROS的破坏。在AIM 3中，我们将展示PDE抑制块SLFN4/SLFN12L+ - MDSC并在胃肿瘤发生的自chtonos模型中调节免疫小组微环境。一个 小鼠模型和人体器官的组合将用于了解潮湿配体在 发生慢性注射后塑造免疫微环境。 SLFN4的有条件删除 人类直系同源物SLFN12L的敲低将用于剖析这些schlapens如何保护ifn- 来自细胞死亡的MDSC敏感。最后，自调节免疫环境时，它发挥了重要作用 在肿瘤生长中的作用，我们将检查破坏或消除这些SLFN4/SLFN12L的小分子 影响肿瘤生长。这些目标的完成将使人们更好地了解这一重要的 免疫调节细胞的子集被小分子诱导，维持和最终靶向。