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.

项目概要 虽然肺癌在美国癌症死亡率中位居首位，但综合死亡率 归因于消化系统疾病中的癌症，其中胃肠道癌症占一半病例，超过 慢性炎症是胃肠道癌症的共同危险因素，可导致 癌前病变的发展（例如，食道、胃和胆道的肠化生） 道，还包括炎症性肠病 (IBD) 中的结肠发育不良相关病变和肿块 (DALM)）。 通过产生更多新知识，加深对慢性炎症如何发展的了解 精确定义导致胃肠道细胞浸润的机制至关重要，因为它打开了胃肠道 发现治疗胃部炎症和肠道炎症的新靶点。 化生-胃癌序列（又名 Correa 级联）已十分成熟，尤其是在螺杆菌中 幽门螺杆菌感染，但目前尚无针对慢性胃炎的有效治疗方法，特别是在观察到慢性胃炎时 幽门螺杆菌根除后或抗生素难治性幽门螺杆菌感染。 我们的新数据表明，黑色素瘤 2 (AIM2) 中不存在幽门螺旋杆菌胃炎的机制尚未被认识。 炎症小体的一部分，有助于宿主防御细菌和病毒，是一个主要的 慢性螺杆菌感染过程中的调控途径 由于 AIM2 的 C 端 HIN 结构域。 结合双链 DNA 并充当胞质 dsDNA 传感器，导致 caspase-的自动激活 1，一种处理促炎细胞因子 IL-1β 的酶，因此我们最初预计 AIM2-/- 小鼠出现不太严重的幽门螺杆菌胃病理然而，我们令人惊讶的数据表明， 与受感染的野生型小鼠相比，受感染的 AIM2-/- 小鼠患有明显更多的胃炎，其特征是 CD8+ 组织驻留记忆 T 细胞 (TRM) 显着增加，这表明 AIM2 有所改善。 胃病理学通过独立于其已知的炎症小体功能的机制进行。 迄今为止的工作强烈暗示 B 细胞中螺杆菌诱导的 AIM2 抑制了 B 细胞的浸润 基于我们的研究，CD8+ TRM 通过负向调节 B 细胞趋化因子（CXCL16 和 CXCL9）的产生。 在本提案中的初步数据中，我们追求胃 B 细胞中 AIM2 的诱导调节 趋化因子（CXCL16 和 CXCL9）介导的 CD8+ 组织滞留导致螺杆菌相关性胃炎 在本提案中，我们将研究 AIM2 如何调节胃 B 细胞功能和 成熟、CD8+ TRM 保留以及幽门螺杆菌病理学与患者 AIM2 突变的相关性。 筛查 AIM2 基因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炎症尤其是以下疾病提供新的靶点： 由 IBD 等 TRM 介导。