Tuftsin prevents the negative immunoregulation of neuropilin-1highCD4+CD25+Regulatory T cells and improves survival rate in septic mice.
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.
Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China.
Yu-Lei
YL
Gao
Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China.
Mu-Ming
MM
Yu
Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China.
Song-Tao
ST
Shou
Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China.
Ying
Y
Yao
Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China.
Yan-Cun
YC
Liu
Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China.
Li-Jun
LJ
Wang
Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China.
Bin
B
Lu
Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China.
Yan-Fen
YF
Chai
D000818:Animals; D060908:CTLA-4 Antigen / Q000378:metabolism; D002478:Cells, Cultured; D019175:DNA Methylation; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D007155:Immunologic Factors / Q000494:pharmacology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008807:Mice, Inbred BALB C; D039942:Neuropilin-1 / Q000276:immunology / Q000378:metabolism*; D018805:Sepsis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014405:Tuftsin / Q000494:pharmacology*
D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C508018:Il2ra protein, mouse; D007155:Immunologic Factors; D053645:Interleukin-2 Receptor alpha Subunit; D016212:Transforming Growth Factor beta; D039942:Neuropilin-1; D014405:Tuftsin
negative immunoregulation; neuropilin-1; regulatory T cells; sepsis; tuftsin