Design principles of NKp46+ ILC-macrophage cross-talk in autoimmune organ damage

NKp46 ILC-巨噬细胞串扰在自身免疫器官损伤中的设计原理

• 批准号: 428195445
• 负责人: Professor Dr. Kevin Thurley
• 金额: --
• 依托单位: Medizinische Klinik mit Schwerpunkt Rheumatologie und Klinische Immunologie (einschließlich Arbeitsbereich Physikalische Medizin)
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/428195445?language=en
• 关键词: Design; principles; NKp46+; ILC; macrophage

Chronic inflammation is a persistent state of the immune system marked by a range of stable changes in set-points with respect to normal tissue homeostasis, such as number, activation state and cellular cross-talk of immune cell populations. In the context of autoimmune disease, acute inflammation can convert to self-sustained chronic inflammation and promote organ damage. The underlying principles that guide this conversion remain largely unexplored, but recent data indicate a pivotal role for NKp46+ innate lymphoid cells (ILC). We propose that ILC drive self-sustained chronic inflammation and autoimmune organ damage in the context of the prototypic autoimmune disease, systemic lupus erythematosus (SLE). Here, we will perform an interdisciplinary study combining kinetic in vivo experiments with data-driven mathematical modeling, to quantify and rationalize the functional role of ILC populations during the transition to chronic inflammation. We will dissect and classify the phenotypic heterogeneity of NKp46+ ILC during development of lupus nephritis, a clinical manifestation of SLE. Data-driven models will be developed to analyze ILC-centered cell-cell communication networks and derive testable predictions regarding network perturbations. Taken together, the proposed research will generate broad quantitative and conceptual insight into the function and interaction networks of ILC in chronic inflammation and autoimmune organ damage.

慢性炎症是免疫系统的持续状态，其特征在于相对于正常组织稳态的设定点的一系列稳定变化，例如免疫细胞群体的数量、激活状态和细胞串扰。在自身免疫性疾病的背景下，急性炎症可以转化为自我持续的慢性炎症并促进器官损伤。指导这种转换的基本原理在很大程度上尚未探索，但最近的数据表明NKp46+先天淋巴细胞（ILC）的关键作用。我们认为ILC在原型自身免疫性疾病系统性红斑狼疮（SLE）的背景下驱动自我持续的慢性炎症和自身免疫性器官损伤。在这里，我们将进行一项跨学科研究，将体内动力学实验与数据驱动的数学建模相结合，以量化和合理化ILC群体在向慢性炎症过渡期间的功能作用。我们将对狼疮性肾炎（SLE的一种临床表现）发展过程中NKp46+ ILC的表型异质性进行解剖和分类。将开发数据驱动模型来分析以ILC为中心的细胞间通信网络，并得出关于网络扰动的可测试预测。总之，拟议的研究将产生广泛的定量和概念性的洞察ILC在慢性炎症和自身免疫性器官损伤中的功能和相互作用网络。