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

我们以前的研究表明，过度分泌IL-18的转基因小鼠的表皮细胞自发发展AD样皮炎的Th 2或IgE反应无关。此外，最近的临床研究表明，血清IL-18水平与AD的疾病严重程度平行。因此，我们假设内源性IL-18有助于AD的发展，特别是内源性AD。有充分的证据表明，金黄色葡萄球菌的皮肤感染可加重临床AD。最近，我们证明了S。金黄色葡萄球菌衍生的蛋白A（SpA）诱导IL-18从皮肤释放。在这里，我们产生了一种新的固有的AD小鼠模型，每天局部应用SpA后，破坏皮肤屏障的洗涤剂（SDS）。AD易感性NC/Nga小鼠显示100%的AD发展，并表现出具有白细胞（包括肥大细胞）密集积聚的皮肤表型。他们表现出升高的血清IL-18水平，但不是IgE。在NC/Nga小鼠应用SpA/SDS后，从其局部淋巴结制备的CD 4 ^+ T细胞产生IFN-γ、IL-3、IL-9和IL-13。由于它们同时产生Th 1-和Th 2-细胞因子，我们建议将它们命名为超级Th 1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积累而完全和部分地阻止AD的发展。因此，IL-18可能是治疗感染相关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.