Dysregulated neutrophil subpopulations as a driving mechanism of liver and gastrointestinal disease in HIV-1-infected individuals

7.项目摘要/摘要。 胃肠道(GI)粘膜损伤和肠道上皮屏障破坏是定义 HIV-1感染的发病机制特点。越来越多的证据表明，中性粒细胞在 在HIV-1感染中胃肠和肝脏损害中的作用。中性粒细胞在HIV-1中渗入胃肠道- 高水平的感染者，他们的存在与上皮屏障的破坏有关， 在动物模型和HIV-1感染患者中，上皮渗透性增加，疾病严重程度增加。 在这一应用中，我们提出了微生物易位和由此产生的系统性先天免疫 循环和肠道相关淋巴组织中中性粒细胞亚群的变化介导的调节失调 (GALT)，肝脏在HIV-1疾病进展中起着重要作用。这个项目的总体目标是 建议将中性粒细胞亚群和网织红细胞增多症的作用定义为 HIV-1感染对胃肠道和肝脏的损害，并确定慢性感染的机制 中性粒细胞在HIV-1感染中的激活，以揭示干预的具体检查点。我们的中央 假设HIV-1感染与特定中性粒细胞的诱导和扩张有关 产生活性氧物种(ROS)能力增强的亚群，并经历NETsis。ROS 而从激活的中性粒细胞释放的网络促进胃肠道粘膜和肝脏的损伤，并推动 HIV-1感染的进展。这一假设是基于我们的初步数据和 最近发表的报告显示了中性粒细胞在HIV-1感染中的关键作用。在预赛中 研究中，我们优化了中性粒细胞的详细表征方法，并证明了来自 HIV-1感染者表现出激活的表型，免疫抑制特性，特异性 转录谱，脱颗粒率增加，并具有较高的抗蚊虫感染能力。特定的 新发现的中性粒细胞亚群的特性强烈表明它们在 HIV-1感染者胃肠道黏膜损伤与肝病发病机制。我们建议 确定特异性中性粒细胞亚群的诱导对肝病进展的影响 经ART治疗的HIV-1感染者，以确定高尔特地区中性粒细胞亚群的特异性 以及HIV-1感染者的肝脏，并确定这些组织中是否存在先天免疫失调 组织中表现出M1和M2表型的组织巨噬细胞的比率发生了变化 导致网织红细胞增多的中性粒细胞吞噬功能降低。这一事件的意义 建议的研究是，一旦确定了中性粒细胞在HIV-1感染进展中的作用，中性粒细胞 致病种群的激活和诱导可以在药理学上有针对性。

7. PROJECT SUMMARY / ABSTRACT. Gastrointestinal (GI) mucosal damage and destruction of the gut epithelial barrier are the defining features of the pathogenesis of HIV-1 infection. Accumulated evidence indicates that neutrophils play a critical role in the gastrointestinal and liver damage in HIV-1 infection. Neutrophils infiltrate the GI tract in HIV-1- infected individuals at high levels and their presence is associated with damage to the epithelial barrier, elevated epithelial permeability, and increased disease severity in animal models and HIV-1-infected patients. In this application, we propose that microbial translocation and the resulting systemic innate immune dysregulation mediated by changes in neutrophil subpopulations in circulation, gut-associated lymphoid tissue (GALT), and liver plays a fundamental role in HIV-1 disease progression. The overall objectives of this proposal are to define the role of neutrophil subpopulations and NETosis as driving mechanisms of gastrointestinal and liver damage in HIV-1 infection and to identify the mechanisms responsible for chronic neutrophilic activation in HIV-1 infection in order to reveal the specific checkpoints for intervention. Our central hypothesis is that HIV-1 infection is associated with the induction and expansion of specific neutrophilic subpopulations with increased capacity to produce reactive oxygen species (ROS) and undergo NETosis. ROS and NETs released from activated neutrophils promote damage in the GI mucosa and liver and drive the progression of HIV-1 infection. This hypothesis has been formulated on the basis of our preliminary data and recently published reports demonstrating the critical role of neutrophils in HIV-1 infection. In preliminary studies, we optimized methods for detailed neutrophil characterization and demonstrated that neutrophils from HIV-1-infected individuals display an activated phenotype, immunosuppressive properties, specific transcriptional profile, increased rate of degranulation, and a high capacity to undergo NETosis. Specific properties of the newly identified neutrophil subpopulations strongly indicate that they play a critical role in damaging GI mucosa and the pathogenesis of liver disease in HIV-1-infected individuals. We propose to determine the effect of induction of specific neutrophil subpopulations on the progression of liver disease in ART-treated HIV-1-infected individuals, to identify specific properties of neutrophil subpopulations in the GALT and liver of HIV-1-infected individuals, and determine whether the innate immune dysregulation in these tissues is associated with a shift in the ratio of tissue macrophages exhibiting M1 versus M2 phenotype resulting in lowered efferocytosis and accumulation of neutrophils undergoing NETosis. The significance of the proposed studies is that once the role of neutrophils in the progression of HIV-1 infection is defined, neutrophil activation and induction of pathogenic populations can be pharmacologically targeted.