The role of Absent in Melanoma 2 (Aim2) in CD8+ T cell regulation and Helicobacter-induced gastric pathology

黑色素瘤 2 缺失 (Aim2) 在 CD8 T 细胞调节和螺杆菌诱导的胃病理学中的作用

• 批准号: 10198725
• 负责人: Mohamad El-Zaatari
• 金额: $ 19.5万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-19 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10198725
• 关键词: AIM2 gene; Antibiotics; B-Lymphocytes; Bacteria; Barrett Esophagus; Binding; Body Surface; C-terminal; CASP1 gene; CD8-Positive T-Lymphocytes; CD8B1 gene; CXCL9 gene; Cancer Etiology; Cell Compartmentation; Cell Maturation; Cell physiology; Cellular Infiltration; Chronic; Chronic Gastritis; Correa cascade; Data; Dendritic Cells; Development; Digestive System Disorders; Enzymes; Epithelial; Epithelial Cells; Functional disorder; Gastritis; Gastrointestinal tract structure; Helicobacter; Helicobacter Infections; Helicobacter pylori; Homing; Host Defense; Immune; Infiltration; Inflammasome; Inflammation; Inflammatory Bowel Diseases; Interleukin-1 beta; Knowledge; Lead; Lesion; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of lung; Mediating; Mus; Mutation; Outcome; Pathology; Patients; Play; Process; Production; Proteins; Refractory; Regulatory Pathway; Risk Factors; Role; Severities; Signal Transduction; Spottings; Stomach; T cell regulation; T memory cell; T-Lymphocyte; Tissues; Virus; Wild Type Mouse; Work; base; biliary tract; chemokine; clinical database; colon dysplasia; cytokine; ds-DNA; effective therapy; gastric intestinal metaplasia; gastric retention; genetic variant; gut bacteria; immunopathology; improved; in vitro testing; infection management; inflammatory disease of the intestine; malignant stomach neoplasm; mortality; novel; pathogen; premalignant; risk sharing; screening; sensor

PROJECT SUMMARY While lung cancer holds the top spot for cancer-causing mortality in the US, the combined mortality attributed to cancers in the digestive diseases, where GI tract cancers account for half of the cases, exceeds that of lung cancer. Chronic inflammation is a shared risk factor for GI tract cancers, which can lead to the development of premalignant lesions (e.g., intestinal metaplasia of the esophagus, stomach, and biliary tract but also colonic dysplasia-associated lesions and mass (DALM) in inflammatory bowel disease (IBD)). Improved understanding of how chronic inflammation develops by generating new knowledge that more precisely defines the mechanisms that lead to cellular infiltration in the GI tract is critical as it opens the door for novel target discovery in treating this condition. In the stomach, the inflammation-intestinal metaplasia-gastric cancer sequence (a.k.a., Correa cascade) is well-established especially in Helicobacter pylori infection but there is currently no effective treatment for chronic gastritis particularly when observed in post-H. pylori eradication or antibiotic refractory H. pylori infection. We proposed a previously unrecognized mechanism of H. pylori gastritis. Our novel data show that Absent In Melanoma 2 (AIM2), a part of the inflammasome that contributes to host defense against bacteria and viruses, is a major regulatory pathway during chronic Helicobacter infection. Because the C-terminal HIN domain of AIM2 binds double-stranded DNA and acts as a cytosolic dsDNA sensor that leads to autoactivation of caspase- 1, an enzyme that processes the proinflammatory cytokine IL-1β, we therefore initially expected AIM2-/- mice to develop less severe Helicobacter gastric pathology. However, our surprising data show that, compared to infected wild-type mice, infected AIM2-/- mice had significantly more gastritis characterized by a significant increase in CD8+ tissue-resident memory T cells (TRM). This suggests that AIM2 ameliorates gastric pathology via a mechanism that is independent of its known inflammasome function. Our related work thus far strongly implicates that Helicobacter-induced AIM2 in B cells suppresses the infiltration of CD8+ TRM by negatively regulating B cell chemokine (CXCL16 and CXCL9) production. Based on our preliminary data in this proposal, we hypothesize that AIM2 induction in gastric B cells regulates Helicobacter-associated gastritis by chemokine (CXCL16 and CXCL9)-mediated retention of CD8+ tissue- resident memory T cell. In this proposal, we will investigate how AIM2 regulates gastric B cell function and maturation, CD8+ TRM retention, and correlate H. pylori pathology to AIM2 mutations in patients. While screening for AIM2 genetic variants may help to predict severe H. pylori complications, completion of the proposed study may also provide novel targets for epithelial inflammation especially conditions that are mediated by TRM such as IBD.

项目摘要 虽然肺癌在美国占死亡率的首位，但综合死亡率 归因于消化系统疾病中的癌症，胃肠道癌占了一半的癌症 肺癌。慢性炎症是胃肠道癌的共同危险因素，这可能导致 前病变的发育（例如食管，胃和胆汁的肠化生 炎症性肠病（IBD）中的结肠发育不良相关病变和肿块（DALM）也是区域。 通过产生更多的知识，对如何发展慢性炎症发展的理解有更多的了解 精确定义导致胃肠道细胞浸润的机制至关重要，因为它打开了 在治疗这种情况下进行新颖目标发现的门。在胃中，炎症肠内 冬季癌症序列（又称Correa级联）尤其是在Helicobacter中， 幽门螺杆菌感染，但目前尚无有效治疗慢性胃炎 在后H中。幽门螺杆菌消除或抗生素难治性幽门螺杆菌感染。我们提出了以前的 幽门螺杆菌胃炎的未识别机制。我们的新数据表明，黑色素瘤2（AIM2）中没有 有助于宿主防御细菌和病毒的炎症小体的一部分是主要的 慢性旋转杆菌感染期间的调节途径。因为AIM2的C末端HIN域 结合双链DNA并充当胞质DSDNA传感器，导致caspase-自动活化 1，一种处理促炎细胞因子IL-1β的酶，我们最初预期的是AIM2 - / - 小鼠会发展出较少严重的胃病胃病理学。但是，我们的惊喜数据表明， 与受感染的野生型小鼠相比，感染的AIM2 - / - 小鼠的胃炎明显更多。 CD8+组织居民记忆T细胞（TRM）的显着增加。这表明AIM2可以改善 胃病理学通过独立于其已知炎性体功能的机制。我们的相关 迄今为止的工作强烈暗示B细胞中的旋律杆菌诱导的AIM2抑制了 通过负调节B细胞趋化因子（CXCL16和CXCL9）产生的CD8+ TRM。基于我们 在此提案中，我们假设胃B细胞的AIM2诱导会调节该提案的初步数据 通过趋化因子（CXCL16和CXCL9）介导的CD8+组织 - 介导的保留趋化因子（CXCL16和CXCL9）与旋律相关的胃炎 居民记忆T单元。在此提案中，我们将调查AIM2如何调节胃B细胞功能和 成熟，CD8+ TRM保留，并将幽门螺杆菌病理学与患者的AIM2突变相关。尽管 筛选AIM2遗传变异可能有助于预测严重的幽门螺杆菌并发症，完成 拟议的研究还可能为上皮感染提供新的目标，尤其是 由TRM介导，例如IBD。