Pathological Analysis of IL-18-dependently induced Atopic dermatitis mediated by Pattern Recognition Receptor Activation.

我们之前的研究表明，从表皮细胞过度分泌IL-18的转基因小鼠会自发发生AD样皮炎，而不依赖Th2或IgE反应。此外，最近的临床研究表明，血清IL-18水平与AD的疾病严重程度呈正相关。因此，我们推测内源性IL-18参与了AD，尤其是内源性AD的发生发展。金黄色葡萄球菌皮肤感染可加重临床AD。最近，我们发现金黄色葡萄球菌衍生蛋白A(SPA)可以诱导皮肤释放IL-18。在这里，我们建立了一种新的内源性AD小鼠模型，通过每天局部应用SPA来破坏皮肤屏障(SDS)。AD易感的NC/NGA小鼠表现出100%的AD发展，并表现为皮肤表型，包括肥大细胞在内的白细胞密集聚集。他们的血清IL-18水平升高，但不显示IgE水平。用SpA/SSD免疫NC/NGA小鼠后，其区域淋巴结中的CD4T细胞产生干扰素-γ、IL-3、IL-9和IL-13。由于它们同时产生Th1和Th2细胞因子，我们建议将它们命名为超级Th1细胞。重要的是，我们发现IL-18或IL-3阻断分别通过抑制这种T细胞分化或肥大细胞聚集来完全和部分地阻止AD的发展。因此，IL-18可能成为治疗感染相关性AD的新靶点。

We previously showed that transgenic mice that over-secrete IL-18 from their epidermal cells spontaneously develop AD-like dermatitis independently of Th2 or IgE response. Furthermore, recent clinical studies revealed that serum levels of IL-18 well parallel with the disease severity of AD. Therefore, we assumed that endogenous IL-18 contributes to the development of AD, particularly intrinsic AD. It is well documented that cutaneous infection with Staphylococcus aureus exacerbates clinical AD. Recently, we demonstrated that S. aureus -derived proteinA (SpA) induces IL-18 release from skin. Here, we generated a novel intrinsic AD mouse model by daily topical application of SpA following destroying skin barrier by detergent (SDS). AD-prone NC/Nga mice showed 100% development of AD and manifested skin phenotypes with dense accumulation of leukocytes including mast cells. They exhibited elevated serum levels of IL-18 but not IgE. After application of NC/Nga mice with SpA/SDS, CD4^+ T cells prepared from their regional lymph nodes produced IFN-γ, IL-3, IL-9 and IL-13. As they produce both Th1- and Th2-cytokines, we proposed to designate them super Th1 cell. Importantly, we found that IL-18 or IL-3 blockade, completely and partly, prevented the AD development by inhibiting this T cell differentiation or the mast cell accumulation, respectively. Thus, IL-18 might be a novel target for the treatment of infection-associated AD.