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

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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.