Abstract
Our previous research showed that neuropilin (Nrp) -1highCD4+CD25+Regulatory T cells (Tregs) exhibited primary negative immunoregulation in sepsis induced immune dysfunction. Tuftsin is the typical ligand of Nrp-1. Herein, we investigated the potential therapeutic value and mechanisms of tuftsin in sepsis. Sepsis per se markedly decreased the serum concentration of tuftsin, administration of tuftsin improved the survival rate of septic mice with cecal ligation and puncture (CLP). In vitro study, tuftsin prevented the negative immunoregulation of Nrp-1highCD4+CD25+Tregs, including weakening the expression of forkhead/winged helix transcription factor (Foxp)- 3/cytotoxic T lymphocyte associated antigen (CTLA)-4, inhibiting the secretion of transforming growth factor (TGF)-β, and weakening the immunosuppressive function of Nrp-1highCD4+CD25+Tregs to conventional CD4+CD25−T cells. Tuftsin markedly inhibited the demethylation of Foxp3-Tregs specific demethylated region (TSDR) of Nrp-1highCD4+CD25+Tregs. Tuftsin could represent a new potential therapeutic agentia to improve the outcome of septic mice, and associate with preventing the negative immunoregulation of Tregs via Nrp-1.
Highlights
Sepsis is still the leading cause of death among critically ill patients in intensive care units, and the quality of life for the survivors would usually be impaired [1,2,3,4,5]
We reported that sepsis per se markedly decreased the serum concentration of tuftsin in a grade- and timedependent pattern, administration of tuftsin improved the survival rate of septic mice after cecal ligation and puncture (CLP), especially 2 mg/kg, which was in accordance with the findings of Baker CC
Another study showed a population of neuropilin -1 (Nrp-1)+Regulatory T cells (Tregs) in human lymph nodes together with the positive expression of forkhead/ winged helix transcription factor- 3 (Foxp-3) that inhibited the proliferative activity of T cells [32]
Summary
Sepsis is still the leading cause of death among critically ill patients in intensive care units, and the quality of life for the survivors would usually be impaired [1,2,3,4,5]. We demonstrated that tuftsin-derived T-peptide had potential effect on adaptive immunity in sepsis, such as lowering the suppressive ability of CD4+CD25+ Tregs on CD4+CD25− T cells [31]. In the present study, using the classical septic model, i.e., CLP, we demonstrated that the serum concentration of tuftsin was significantly decreased, and the expression of Nrp-1 was significantly enhanced in a grade- and timedependent manner. Tuftsin prevented the negative immunoregulation of Tregs, the primary subtype is Nrp1highCD4+CD25+Tregs, including down-regulating the expression of Foxp-3/CTLA-4, inhibiting the secretion of TGF-β, and down-regulating the immunosuppressive function of Nrp-1highCD4+CD25+Tregs to conventional CD4+CD25-T cells. In vitro and vivo study, tuftsin markedly inhibited the demethylation of Foxp3-TSDR of Nrp-1highCD4+CD25+Tregs in a dose-dependent manner. Tuftsin could represent a new potential therapeutic agentia to improve the outcome of septic mice, and prevent the negative immunoregulation of regulatory T cells via Nrp-1
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