Open AccessTargeting Neuropilin-1 Suppresses the Stability of CD4 + CD25 + Regulatory T Cells via the NF-κB Signaling Pathway in Sepsis
Author(s) -
Yulei Gao,
Chun-xue Wang,
Zi-yi Wang,
Wenjie Li,
Yan-Cun Liu,
Songtao Shou,
Yifeng Chai
Publication year - 2021
Publication title -
infection and immunity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.508
H-Index - 220
eISSN - 1070-6313
pISSN - 0019-9567
DOI - 10.1128/iai.00399-20
Subject(s) - pyrrolidine dithiocarbamate , il 2 receptor , biology , sepsis , signal transduction , microbiology and biotechnology , nf κb , cancer research , immunology , t cell , immune system
Neuropilin-1 (Nrp-1) contributes to maintaining the stability of CD4 + CD25 + regulatory T cells (T regs ). We investigated the impact of Nrp-1 on the stability of CD4 + CD25 + T regs , and the underlying signaling pathways, in a model of sepsis. Splenic CD4 + CD25 + T regs were either treated with anti-Nrp-1, transfected to silence Nrp-1 and inhibitor of NF-κB kinase subunit beta (IKKβ), or administered ammonium pyrrolidine dithiocarbamate (PDTC), followed by recombinant semaphorin 3A (rSema3A), in a simulation of sepsis. After the creation of a sepsis model in mice, anti-Nrp-1 was administered. The expression of the gene encoding forkhead box protein P-3 foxp3-T reg -specific demethylated region ( foxp3-TSDR ), the apoptosis rate, the expression of Foxp-3, cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), and transforming growth factor β1 (TGF-β1), interleukin 10 (IL-10) and TGF-β1 secretion, and the NF-κB signaling activity of CD4 + CD25 + T regs were determined. Sepsis simulation with or without rSema3A increased the stability of CD4 + CD25 + T regs , including an increase in the expression of Foxp-3, CTLA-4, and TGF-β1, decreases in apoptosis and the methylation of foxp3-TSDR , increases in the secretion of TGF-β1 and IL-10, and an increase in the immunosuppressive effect on CD4 + T lymphocytes. Silencing of Nrp-1 or anti-Nrp-1 treatment abrogated lipopolysaccharide (LPS) stimulation with or without an rSema3A-mediated effect. Sepsis simulation increased the DNA-binding activity of NF-κB, as well as the ratios of phosphorylated IKKβ (p-IKKβ) to IKKβ and p-P65 to P65 in vitro and vivo Silencing of IKKβ expression or PDTC treatment suppressed the stability of CD4 + CD25 + T regs in LPS-induced sepsis. Weakening Nrp-1 reduced the stability of CD4 + CD25 + T regs by regulating the NF-κB signaling pathway; thus, Nrp-1 could be a new target for immunoregulation in sepsis.