Natural Killer Cell Regulation of Skin Inflammation

点击翻译按钮获取中文摘要

PROJECT SUMMARY Characterized by chronic skin inflammation, atopic dermatitis (AD) is the most common chronic illness of childhood and is often a lifelong disease. Numerous immune cell types have been implicated in AD pathogenesis, including mast cells, basophils, and T helper type 2 (Th2) cells. Recent studies by the Kim Lab identified group 2 innate lymphoid cells (ILC2s) as critical contributors to development of AD/AD-like disease through production of the type 2 cytokines IL-4 and IL-13. Indeed, blockade of the IL-4 and IL-13 receptor (IL- 4R) has emerged as the first FDA-approved targeted therapy for moderate-to-severe AD. Despite this major advance, <40% of AD patients in phase III clinical trials met the primary endpoint in terms of disease improvement. Development of new AD therapies is hindered by an incomplete understanding of the immune cell types that regulate the disease beyond type 2 immune cells. There is an urgent need to correct this knowledge gap to develop effective therapies for AD. Our long-term goal is to target immune regulators of AD to develop new therapies. The overall objective of our proposal is to identify the immune cell types and effector mechanisms that regulate AD-like disease. Our central hypothesis is that circulating natural killer (NK) cells are major regulators of type 2 inflammation in the skin that can be harnessed to treat AD. NK cells have been implicated in antitumor and antiviral immunity through their production of cytolytic proteins as well as interferon- gamma (IFN-). Recent studies suggest that NK cells may negatively regulate ILC2s in the lung, but the role of NK cells in the skin and AD remains unclear. In preliminary studies, we revealed that mouse NK cells critically suppress skin ILC2 responses in vivo. In humans, we identified that circulating blood NK cells are markedly deficient in moderate-to-severe AD and increase with disease resolution. The rationale for this proposal is that once it is understood how NK cells influence AD pathogenesis, these mechanisms can be harnessed to create effective and novel AD therapies.