Mannan induces ROS-regulated, IL-17A-dependent psoriasis arthritis-like disease in mice
Mannan induces ROS-regulated, IL-17A-dependent psoriasis arthritis-like disease in mice
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DOI：
10.1073/pnas.1405798111
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发表时间：
2014-09-02
影响因子：
11.1
通讯作者：
Holmdahl, Rikard
中科院分区：
文献类型：
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作者：
Khmaladze, Ia;Kelkka, Tiina;Holmdahl, Rikard
银屑病 (Ps) 和银屑病关节炎 (PsA) 是人们知之甚少的常见疾病，由未知的环境因素诱发，影响皮肤和关节。单个 ip。接触来自酿酒酵母的甘露聚糖会在类似于人类 Ps 和 PsA 样疾病的近交小鼠品系中诱发急性炎症，而多次注射则会诱发疾病复发。在缺乏活性氧（ROS）生成的小鼠中观察到疾病严重程度恶化。有趣的是，恢复活性氧的产生，特别是在巨噬细胞中，可以改善皮肤和关节疾病。主要由 γ δ T 细胞产生的 IL-17A 的中和可完全阻断疾病症状。此外，粒细胞耗尽的小鼠能够抵抗疾病的发展。相比之下，某些急性炎症介质（C5、Fc γ 受体 III、肥大细胞和组胺）和适应性免疫参与者（α、β T 和 B 细胞）在疾病诱导中是多余的。因此，我们提出甘露聚糖诱导的巨噬细胞活化导致TNF-α分泌并刺激局部γδT细胞分泌IL-17A。活化的巨噬细胞和原位产生的IL-17A联合作用，驱动中性粒细胞浸润皮肤表皮和真皮，导致疾病表现。因此，我们的发现提出了一种由暴露于外源微生物成分（例如甘露聚糖）触发的新机制，该机制可以诱导并加剧 Ps 和 PsA。
Psoriasis (Ps) and psoriasis arthritis (PsA) are poorly understood common diseases, induced by unknown environmental factors, affecting skin and articular joints. A single i.p. exposure to mannan from Saccharomyces cerevisiae induced an acute inflammation in inbred mouse strains resembling human Ps and PsA-like disease, whereas multiple injections induced a relapsing disease. Exacerbation of disease severity was observed in mice deficient for generation of reactive oxygen species (ROS). Interestingly, restoration of ROS production, specifically in macrophages, ameliorated both skin and joint disease. Neutralization of IL-17A, mainly produced by gamma delta T cells, completely blocked disease symptoms. Furthermore, mice depleted of granulocytes were resistant to disease development. In contrast, certain acute inflammatory mediators (C5, Fc gamma receptor III, mast cells, and histamine) and adaptive immune players (alpha beta T and B cells) were redundant in disease induction. Hence, we propose that mannan-induced activation of macrophages leads to TNF-alpha secretion and stimulation of local gamma delta T cells secreting IL-17A. The combined action of activated macrophages and IL-17A produced in situ drives neutrophil infiltration in the epidermis and dermis of the skin, leading to disease manifestations. Thus, our finding suggests a new mechanism triggered by exposure to exogenous microbial components, such as mannan, that can induce and exacerbate Ps and PsA.