Microbial triggers and molecular mechanisms of Th17 mediated airway inflammation-Resubmission-1

 描述(由申请人提供)：T细胞驱动的炎症是几种炎症性呼吸道疾病的关键组成部分，包括慢性阻塞性肺疾病(COPD)。最近发现的一个效应T细胞亚群，称为T辅助类型(Th)-17细胞，与包括COPD在内的许多慢性炎症性疾病的发病机制有关。然而，这些细胞在慢性呼吸道炎症中的作用仍有待阐明。Th17细胞分泌细胞因子IL-17和IL-22，这些细胞因子作用于周围的上皮细胞和内皮细胞，以及常驻抗原提呈细胞，从而诱导炎性细胞因子和 趋化因子，导致其他炎症细胞的招募，包括中性粒细胞。肠腔内Th17细胞的分化与特定的微生物区系密切相关。然而，其他粘膜部位的微生物群，如呼吸道，是否与其他部位的Th17细胞的分化密切相关尚不清楚。呼吸道中性粒细胞增多是慢性阻塞性肺疾病的常见特征，与肺功能下降相平行。此外，慢性阻塞性肺疾病患者下呼吸道的细菌负荷往往很高，呼吸道定植的程度与肺功能下降和合并发病率增加密切相关。我们最近对一群吸烟者(这是一个患COPD的高危人群)进行的分析显示，呼吸道微生物区系的明显变化与气道中促炎症细胞因子水平的升高和Th17细胞的增加密切相关。基于肠道微生物区系在炎症性肠病等疾病的黏膜免疫反应形成中的关键作用这一范式，根据我们的初步研究，我们假设呼吸道微生物区系在指导Th17细胞分化方面发挥核心作用，Th17细胞反过来促进COPD患者的慢性气道中性粒细胞增多。为了检验这一点，我们将评估一组独特的无症状吸烟者和患有COPD的吸烟者的呼吸道微生物区系、细胞因子和T细胞群。为了进一步探讨呼吸道微生物区系、Th17细胞和呼吸道炎症之间的联系，我们将利用我们新的小鼠模型，该模型产生的呼吸道炎症使人想起COPD中的慢性呼吸道炎症。我们将使用这个小鼠模型和香烟烟雾吸入模型，从机制上深入了解Th17产生的IL-17和IL-22在气道中性粒细胞增多、粘液产生、重塑、肺气肿和相关的肺功能异常中的作用。此外，我们将利用我们的无菌设施来检查呼吸道微生物区系和细菌产物在驱动Th17介导的呼吸道炎症和COPD发病机制中的贡献。我们将通过将细菌群落或热致死细菌重新引入最近再生的无菌小鼠来实现这一点。这些研究将为微生物区系、Th17介导的呼吸道炎症和COPD发病机制之间的联系提供新的见解。

 DESCRIPTION (provided by applicant): T cell-driven inflammation is a key component of several inflammatory airway diseases, including chronic obstructive pulmonary disease (COPD). A recently identified subset of effector T cells, known as T helper type (Th)-17 cells, has been implicated in the pathogenesis of a number of chronic inflammatory conditions, including COPD. Yet, the role of these cells in chronic airway inflammation remains to be elucidated. Th17 cells secrete the cytokines IL-17 and IL-22 which act on surrounding epithelial and endothelial cells, as well as on resident antigen presenting cells, to elicit production of inflammatory cytokines and chemokines, leading to the recruitment of other inflammatory cells, including neutrophils. Differentiation of Th17 cells in the gut lumen has been closely linked to specific microbiota. However, whether the microbiome of other mucosal sites, such as the airways, is intimately linked to differentiation of Th17 cells at other sites is unknown. Airway neutrophilia is a common feature of COPD that parallels decline in lung function. Furthermore, COPD patients often present with high bacterial burden in the lower airways and the extent of airway colonization is closely associated with reduced lung function and enhanced co-morbidity. Our recent analysis of a cohort of smokers, a population that is at high risk of developing COPD, revealed that a distinct repertoire of airway microbiota is closely associated with elevated levels of pro-inflammatory cytokines and increased Th17 cells in the airways. Based on the paradigm that gut microbiota are critical in shaping the mucosal immune response in diseases such as inflammatory bowel disease, and in light of our preliminary studies, we hypothesize that airway microbiota plays a central role in directing the differentiation of Th17 cells, which in turn promoe chronic airway neutrophilia in COPD. To examine this, we will assess airway microbiota, cytokines and T cell populations in a unique cohort of asymptomatic smokers and smokers that develop COPD. To interrogate the connection between airway microbiota, Th17 cells and airway inflammation further we will take advantage of our novel mouse model that develops airway inflammation reminiscent of chronic airway inflammation seen in COPD. We will use this mouse model and a cigarette smoke inhalation model to gain mechanistic insight into the contribution of Th17-produced IL-17 and IL-22 to airway neutrophilia, mucus production, remodeling, emphysema and associated abnormalities in lung function. Furthermore, we will take advantage of our germ free facility to examine the contribution of airway microbiota and bacterial products in driving Th17-mediated airway inflammation and pathogenesis of COPD. We will accomplish this through re-introduction of bacterial communities or heat-killed bacteria into the recently rederived germ-free mice. These studies will provide new insight into the link between microbiota, Th17-mediated airway inflammation and COPD pathogenesis.