PMID- 29922290
OWN - NLM
STAT- MEDLINE
DCOM- 20190809
LR  - 20190809
IS  - 1664-3224 (Print)
IS  - 1664-3224 (Electronic)
IS  - 1664-3224 (Linking)
VI  - 9
DP  - 2018
TI  - An Immunosuppressive Tick Salivary Gland Protein DsCystatin Interferes With 
      Toll-Like Receptor Signaling by Downregulating TRAF6.
PG  - 1245
LID - 10.3389/fimmu.2018.01245 [doi]
LID - 1245
AB  - 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 
      IL1beta, IFNgamma, TNFalpha, 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 NFkappaB 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 
      IkappaBalpha and the nuclear transport of NFkappaB. 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.
FAU - Sun, Ta
AU  - Sun T
AD  - Institutes of Biology and Medical Sciences, Jiangsu Key Laboratory of Infection 
      and Immunity, Soochow University, Suzhou, China.
FAU - Wang, Fanqi
AU  - Wang F
AD  - Institutes of Biology and Medical Sciences, Jiangsu Key Laboratory of Infection 
      and Immunity, Soochow University, Suzhou, China.
FAU - Pan, Wen
AU  - Pan W
AD  - Institutes of Biology and Medical Sciences, Jiangsu Key Laboratory of Infection 
      and Immunity, Soochow University, Suzhou, China.
FAU - Wu, Qihan
AU  - Wu Q
AD  - Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, RID, Fudan Unversity, 
      Shanghai, China.
FAU - Wang, Jingwen
AU  - Wang J
AD  - School of Life Science, Fudan University, Shanghai, China.
FAU - Dai, Jianfeng
AU  - Dai J
AD  - Institutes of Biology and Medical Sciences, Jiangsu Key Laboratory of Infection 
      and Immunity, Soochow University, Suzhou, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180601
PL  - Switzerland
TA  - Front Immunol
JT  - Frontiers in immunology
JID - 101560960
RN  - 0 (Cystatins)
RN  - 0 (NF-kappa B)
RN  - 0 (Recombinant Proteins)
RN  - 0 (TNF Receptor-Associated Factor 6)
RN  - 0 (Toll-Like Receptors)
RN  - EC 3.4.22.1 (Cathepsin B)
RN  - EC 3.4.22.15 (Cathepsin L)
MH  - Animals
MH  - Arthritis, Infectious/drug therapy/microbiology/pathology
MH  - Autophagy
MH  - Cathepsin B/metabolism
MH  - Cathepsin L/metabolism
MH  - Cystatins/genetics/isolation & purification/*metabolism/pharmacology
MH  - Dendritic Cells/drug effects/immunology/metabolism
MH  - Dermacentor
MH  - Immunomodulation/drug effects
MH  - Macrophages/drug effects/immunology/metabolism
MH  - Mice
MH  - NF-kappa B/metabolism
MH  - Protein Binding
MH  - Protein Transport
MH  - Recombinant Proteins
MH  - Salivary Glands/immunology/*metabolism
MH  - *Signal Transduction
MH  - TNF Receptor-Associated Factor 6/*metabolism
MH  - Ticks/immunology/*metabolism
MH  - Toll-Like Receptors/*metabolism
PMC - PMC5996936
OTO - NOTNLM
OT  - TLR signaling
OT  - cystatin
OT  - immunosuppressant
OT  - inflammation
OT  - tick
EDAT- 2018/06/21 06:00
MHDA- 2018/06/21 06:01
PMCR- 2018/01/01
CRDT- 2018/06/21 06:00
PHST- 2018/02/28 00:00 [received]
PHST- 2018/05/17 00:00 [accepted]
PHST- 2018/06/21 06:00 [entrez]
PHST- 2018/06/21 06:00 [pubmed]
PHST- 2018/06/21 06:01 [medline]
PHST- 2018/01/01 00:00 [pmc-release]
AID - 10.3389/fimmu.2018.01245 [doi]
PST - epublish
SO  - Front Immunol. 2018 Jun 1;9:1245. doi: 10.3389/fimmu.2018.01245. eCollection 
      2018.