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

慢性炎症是免疫系统的一种持续状态，其特征是与正常组织稳态相关的一系列设定值的稳定变化，如免疫细胞群的数量、激活状态和细胞串扰。在自身免疫性疾病的情况下，急性炎症可转化为自我持续的慢性炎症并促进器官损伤。指导这种转化的基本原理在很大程度上仍未被探索，但最近的数据表明NKp46+先天淋巴样细胞（ILC）起着关键作用。我们提出ILC在典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的研究，结合体内动力学实验和数据驱动的数学模型，量化和合理化ILC群体在向慢性炎症过渡过程中的功能作用。我们将解剖和分类NKp46+ ILC在狼疮肾炎（SLE的临床表现）发展过程中的表型异质性。将开发数据驱动模型来分析以ilc为中心的细胞-细胞通信网络，并得出关于网络扰动的可测试预测。综上所述，拟议的研究将对ILC在慢性炎症和自身免疫器官损伤中的功能和相互作用网络产生广泛的定量和概念性见解。

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.