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

7.项目总结/摘要。 胃肠道（GI）粘膜损伤和肠道上皮屏障的破坏是定义 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感染的胃肠道和肝脏损伤中的作用。中性粒细胞浸润胃肠道在HIV-1- 高水平的感染个体，并且它们的存在与上皮屏障的损伤有关， 在动物模型和HIV-1感染患者中，上皮通透性升高，疾病严重程度增加。 在这个应用中，我们提出微生物易位和由此产生的系统性先天免疫 由循环、肠道相关淋巴组织中中性粒细胞亚群变化介导的调节异常 （GALT），肝脏在HIV-1疾病进展中起着重要作用。这一总体目标 建议将中性粒细胞亚群和NETosis的作用定义为 胃肠道和肝脏损害的HIV-1感染，并确定机制负责慢性 HIV-1感染中的嗜中性粒细胞活化，以揭示干预的具体检查点。我们的中央 一种假说认为HIV-1感染与特异性嗜酸性粒细胞的诱导和扩增有关， 具有增加的产生活性氧（ROS）和经历NETosis的能力的亚群。ROS 从活化的中性粒细胞释放的NET促进胃肠道粘膜和肝脏的损伤， HIV-1感染的进展。这一假设是根据我们的初步数据提出的， 最近发表的报告证明了中性粒细胞在HIV-1感染中的关键作用。初步 研究中，我们优化了详细的中性粒细胞表征方法，并证明中性粒细胞从 HIV-1感染者表现出活化的表型、免疫抑制特性、特异性 转录谱，增加的脱粒速率，和经历NETosis的高能力。具体 新鉴定的中性粒细胞亚群的性质强烈表明它们在 胃肠道粘膜损伤和HIV-1感染者肝脏疾病的发病机制。我们建议 确定诱导特定中性粒细胞亚群对肝脏疾病进展的影响， ART治疗的HIV-1感染者，以确定GALT中中性粒细胞亚群的特异性 和肝脏的HIV-1感染者，并确定是否先天免疫失调，在这些 组织与表现出M1与M2表型的组织巨噬细胞比率的变化相关 导致经历NETosis的嗜中性粒细胞减少和积聚。的意义 一项提议的研究是，一旦确定了中性粒细胞在HIV-1感染进展中的作用， 病原群体的激活和诱导可以是靶向的。

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.