An Immunosuppressive Tick Salivary Gland Protein DsCystatin Interferes With Toll-Like Receptor Signaling by Downregulating TRAF6
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 Dermacentor silvarum of China. D...
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doaj-1084c76342914435ae27ce8ba63b39d92020-11-24T23:15:31ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-06-01910.3389/fimmu.2018.01245361960An Immunosuppressive Tick Salivary Gland Protein DsCystatin Interferes With Toll-Like Receptor Signaling by Downregulating TRAF6Ta Sun0Fanqi Wang1Wen Pan2Qihan Wu3Jingwen Wang4Jianfeng Dai5Institutes of Biology and Medical Sciences, Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou, ChinaInstitutes of Biology and Medical Sciences, Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou, ChinaInstitutes of Biology and Medical Sciences, Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou, ChinaKey Laboratory of Reproduction Regulation of NPFPC, SIPPR, RID, Fudan Unversity, Shanghai, ChinaSchool of Life Science, Fudan University, Shanghai, ChinaInstitutes of Biology and Medical Sciences, Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou, ChinaTicks, 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 Dermacentor 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 IL1β, IFNγ, TNFα, 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 NFκB 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 IκBα and the nuclear transport of NFκB. 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.https://www.frontiersin.org/article/10.3389/fimmu.2018.01245/fulltickcystatinimmunosuppressantTLR signalinginflammation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ta Sun Fanqi Wang Wen Pan Qihan Wu Jingwen Wang Jianfeng Dai |
spellingShingle |
Ta Sun Fanqi Wang Wen Pan Qihan Wu Jingwen Wang Jianfeng Dai An Immunosuppressive Tick Salivary Gland Protein DsCystatin Interferes With Toll-Like Receptor Signaling by Downregulating TRAF6 Frontiers in Immunology tick cystatin immunosuppressant TLR signaling inflammation |
author_facet |
Ta Sun Fanqi Wang Wen Pan Qihan Wu Jingwen Wang Jianfeng Dai |
author_sort |
Ta Sun |
title |
An Immunosuppressive Tick Salivary Gland Protein DsCystatin Interferes With Toll-Like Receptor Signaling by Downregulating TRAF6 |
title_short |
An Immunosuppressive Tick Salivary Gland Protein DsCystatin Interferes With Toll-Like Receptor Signaling by Downregulating TRAF6 |
title_full |
An Immunosuppressive Tick Salivary Gland Protein DsCystatin Interferes With Toll-Like Receptor Signaling by Downregulating TRAF6 |
title_fullStr |
An Immunosuppressive Tick Salivary Gland Protein DsCystatin Interferes With Toll-Like Receptor Signaling by Downregulating TRAF6 |
title_full_unstemmed |
An Immunosuppressive Tick Salivary Gland Protein DsCystatin Interferes With Toll-Like Receptor Signaling by Downregulating TRAF6 |
title_sort |
immunosuppressive tick salivary gland protein dscystatin interferes with toll-like receptor signaling by downregulating traf6 |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2018-06-01 |
description |
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 Dermacentor 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 IL1β, IFNγ, TNFα, 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 NFκB 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 IκBα and the nuclear transport of NFκB. 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. |
topic |
tick cystatin immunosuppressant TLR signaling inflammation |
url |
https://www.frontiersin.org/article/10.3389/fimmu.2018.01245/full |
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