Phenotype and function of innate lymphoid cells in cystic fibrosis lung disease

囊性纤维化是北欧和中欧最常见的常染色体隐性遗传性进行性肺部疾病。Cf肺部疾病的特点是炎症和感染的恶性循环，导致肺组织逐渐破坏。这种中性粒细胞炎症对肺组织的破坏决定了疾病的进程，并仍然缩短了囊性纤维化患者的预期寿命。因此，抗炎方法是以患者为中心的CF研究的中心问题，特别是众所周知的抗炎药物，如类固醇，到目前为止还没有显示出足够的抗炎作用。ILCs有助于对CF肺部疾病中急、慢性呼吸道感染所特有的各种细菌和真菌感染的早期免疫防御，如铜绿假单胞菌或烟曲霉。固有淋巴样细胞(ILCs)是位于粘膜表面下的组织内淋巴细胞，对控制ILCs扩张和分化的上皮信号作出反应。ILC反过来通过控制免疫系统中其他效应细胞的扩张和分化来促进免疫防御机制，并可能支持免疫记忆的形成。ILCs通过分泌细胞因子和表面分子，如共刺激分子、MHCII和检查点抑制分子等来介导这些效应。我们在CF肺组织和类CF小鼠模型中的初步数据表明，ILC在CF肺部疾病的中性粒细胞炎症的发展中起着重要作用。然而，目前还不清楚哪些ILC来源的信号是中性粒细胞肺炎性疾病的基础。此外，感染性和/或过敏性刺激对ILC在CF肺部疾病中的作用尚未得到解决。ILC效应功能对分泌的细胞因子和表面分子的依赖性表明，适当的方法来调节ILC相关的细胞因子和/或表面分子可能是一种有希望的靶向中性粒细胞炎症反应的方法来影响CF肺部疾病。因此，对于这一建议，我们的目标是通过全面描述CF肺组织和类CF小鼠模型中的细胞因子和表面分子以及其他信号通路，来确定CF肺部疾病的ILC相关介质。在第二步中，我们建议评估这些介质在适当的小鼠模型和细胞培养系统中的功能相关性，以便为进一步的临床前和临床研究提供基础，旨在调节ILC介导的炎症反应在CF肺部疾病中的作用。

Cystic fibrosis (CF) is the most common autosomal recessive progressive lung disease in Northern and Central Europe. CF lung disease is characterized by a vicious cycle of inflammation and infection that leads to progressive destruction of lung tissue. This destruction of lung tissue by a neutrophilic inflammation determines the course of the disease and still shortens the life expectancy of patients with cystic fibrosis. Anti-inflammatory approaches are therefore a central concern of patient-oriented CF research, especially as well-known anti-inflammatory drugs, such as steroids, have so far failed to show sufficient anti-inflammatory effects on CF lung disease.ILCs contribute to the early immune defense of a variety of bacterial and fungal infections characteristic of the acute and chronic respiratory tract infections in CF lung disease, e.g. Pseudomonas aeruginosa or Aspergillus fumigatus. As tissue-resident lymphocytes located beneath the mucosal surface, innate lymphoid cells (ILCs) respond to epithelial signals that control the expansion and differentiation of ILCs. ILCs in turn contribute to immune defense mechanisms by controlling the expansion and differentiation of other effector cells of the immune system and possibly support the formation of immunological memory. ILCs mediate these effects by cytokine secretion and surface molecules, such as costimulatory molecules, MHCII and checkpoint inhibitor molecules. Our preliminary data in CF lung tissue and CF-like mouse models suggest that ILCs contribute to the development of neutrophilic inflammation in CF lung disease. However, it has not yet been clarified which ILC-derived signals underlie neutrophilic lung inflammation in CF lung disease. Furthermore, the role of infectious and/or allergic stimuli for the contribution of ILCs to CF lung disease has not been addressed.The dependence of ILC effector function on secreted cytokines and surface molecules suggests that appropriate approaches to modulate ILC-associated cytokines and / or surface molecules may be a promising approach to target the neutrophil inflammatory response to influence CF lung disease. For this proposal, we therefore aim to identify ILC-associated mediators of CF lung disease by a comprehensive characterization of the repertoire of cytokines and surface molecules and other signaling pathways of CF lung tissue and CF-like mouse models. In a second step, we propose to assess the functional relevance of these mediators in appropriate mouse models and cell culture systems in order to provide a basis for further pre-clinical and clinical studies aimed at modulating the ILC-mediated inflammatory response in CF lung disease.