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 Dermaceotor silvarum 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 IL1 beta, IFN gamma, TNF alpha, and IL6 from mouse bone marrow-derived macrophages (BMDMs) that had been stimulated with LPS or Borrelia burgdorferi, 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 B. burgdorferi-induced NF kappa B activation. For the first time, we identified that DsCystatin-attenuated TLR4 signaling by targeting TRAF6. DsCystatin enhanced LPS-induced autophagy, mediated TRAF6 degradation via an autophagy dependent manner, thereby impeded the downstream phosphorylation of I kappa B alpha and the nuclear transport of NF kappa B. Finally, DsCystatin relieved the joint inflammation in B. burgdorferi 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.
[1]Soochow Univ, Jiangsu Key Lab Infect & Immun, Inst Biol, Suzhou, Peoples R China;
[2]Soochow Univ, Jiangsu Key Lab Infect & Immun, Inst Med Sci, Suzhou, Peoples R China;
[3]Fudan Unvers, RID, SIPPR, Key Lab Reprod Regulat NPFPC, Shanghai, Peoples R China;
[4]Fudan Univ, Sch Life Sci, Shanghai, Peoples R China
(8.0+极速模式)