Institutes of Biology and Medical Sciences, Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou, China.
Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, RID, Fudan Unversity, Shanghai, China.
Front Immunol. 2018 Jun 1;9:1245. doi: 10.3389/fimmu.2018.01245. eCollection 2018.
Ticks, blood-feeding arthropods, and secrete immunosuppressive molecules that inhibit host immune responses and provide survival advantages to pathogens. In this study, we characterized the immunosuppressive function of a novel tick salivary protein, DsCystatin, from of China. DsCystatin directly interacted with human Cathepsins L and B and inhibited their enzymatic activities. DsCystatin impaired the expression of inflammatory cytokines such as IL1β, IFNγ, TNFα, and IL6 from mouse bone marrow-derived macrophages (BMDMs) that had been stimulated with LPS or . Consistently, DsCystatin inhibited the activation of mouse BMDMs and bone marrow-derived dendritic cells by downregulating the surface expression of CD80 and CD86. Mechanically, DsCystatin inhibited LPS- or -induced NFκB activation. For the first time, we identified that DsCystatin-attenuated TLR4 signaling by targeting TRAF6. DsCystatin enhanced LPS-induced autophagy, mediated TRAF6 degradation an autophagy dependent manner, thereby impeded the downstream phosphorylation of IκBα and the nuclear transport of NFκB. Finally, DsCystatin relieved the joint inflammation in or complete Freund's adjuvant induced mouse arthritis models. These data suggested that DsCystatin is a novel immunosuppressive protein and can potentially be used in the treatment of inflammatory diseases.
蜱虫是吸血节肢动物，会分泌抑制宿主免疫反应的免疫抑制分子，为病原体的生存提供优势。在这项研究中，我们对来自中国的一种新型蜱唾液蛋白 DsCystatin 的免疫抑制功能进行了表征。DsCystatin 直接与人类组织蛋白酶 L 和 B 相互作用并抑制其酶活性。DsCystatin 损害了 LPS 或 刺激的小鼠骨髓来源的巨噬细胞 (BMDM) 中炎性细胞因子如 IL1β、IFNγ、TNFα 和 IL6 的表达。同样，DsCystatin 通过下调 CD80 和 CD86 的表面表达来抑制小鼠 BMDM 和骨髓来源树突状细胞的激活。在机制上，DsCystatin 通过靶向 TRAF6 抑制 LPS 或 诱导的 NFκB 激活。我们首次发现 DsCystatin 通过靶向 TRAF6 来减弱 TLR4 信号。DsCystatin 增强 LPS 诱导的自噬，通过自噬依赖性方式介导 TRAF6 降解，从而阻碍 IκBα 的下游磷酸化和 NFκB 的核转运。最后，DsCystatin 缓解了 或完全弗氏佐剂诱导的小鼠关节炎模型中的关节炎症。这些数据表明 DsCystatin 是一种新型的免疫抑制蛋白，可潜在用于治疗炎症性疾病。
