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

项目摘要 虽然肺癌在美国癌症死亡率中占据首位，但 消化系统疾病中的癌症，其中胃肠道癌症占一半， 就是肺癌。慢性炎症是胃肠道癌症的一个共同风险因素，这可能导致 恶化前病变的发展（例如，食管、胃和胆道的肠上皮化生 炎症性肠病（IBD）中的结肠发育不良相关病变和肿块（DALM））。 通过产生更多的新知识， 精确定义导致胃肠道细胞浸润的机制是至关重要的，因为它打开了 在治疗这种疾病中发现新靶点的大门。在胃里，炎症-肠道 化生-胃癌序列（也称为，Correa级联反应）是公认的，尤其是在螺杆菌中 幽门螺杆菌感染，但目前没有有效的治疗慢性胃炎，特别是当观察到 在H.根除幽门螺杆菌或抗生素难治性幽门螺杆菌。幽门感染我们之前提出了一个 未被认识的H.幽门胃炎我们的新数据显示，黑色素瘤中缺失2（AIM 2）， 炎性小体的一部分，有助于宿主防御细菌和病毒，是一个主要的 慢性螺杆菌感染的调控途径。因为AIM 2的C-末端HIN结构域 结合双链DNA，并作为胞质dsDNA传感器，导致半胱天冬酶的自激活， 1，一种处理促炎细胞因子IL-1β的酶，因此我们最初预期AIM 2-/- 小鼠发展不太严重的螺杆菌胃病理。然而，令人惊讶的数据显示， 与感染的野生型小鼠相比，感染的AIM 2-/-小鼠具有显著更多的胃炎，其特征在于 CD 8+组织驻留记忆T细胞（TRM）的显著增加。这表明AIM 2改善了 通过独立于其已知炎性体功能的机制引起胃病理学改变。我们的相关 迄今为止的工作强烈暗示，在B细胞中，螺杆菌诱导的AIM 2抑制了 通过负调节B细胞趋化因子（CXCL 16和CXCL 9）的产生来调节CD 8 + TRM。基于我们 在这个提议的初步数据中，我们假设胃B细胞中的AIM 2诱导调节了 趋化因子（CXCL 16和CXCL 9）介导的CD 8+组织滞留导致的螺杆菌相关性胃炎- 常驻记忆T细胞在这个提议中，我们将研究AIM 2如何调节胃B细胞功能， 成熟，CD 8 + TRM保留，以及相关的H。pylori病理与患者的AIM 2突变有关。而 筛查AIM 2基因变异可能有助于预测严重的H.幽门螺杆菌并发症，完成 拟议的研究还可能为上皮炎症提供新的靶点，特别是 如IBD等。

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.