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  • Title: Toll-like receptor 4 deficiency increases resistance in sepsis-induced immune dysfunction.
    Author: Cao C, Chai Y, Shou S, Wang J, Huang Y, Ma T.
    Journal: Int Immunopharmacol; 2018 Jan; 54():169-176. PubMed ID: 29149705.
    Abstract:
    Sepsis constitutes a serious life-threatening syndrome associated with complications of deregulated inflammatory response against endotoxin/lipopolysaccharide (LPS)-mediated severe infection. Toll-like receptor 4 (TLR4) plays a critical role in the activation of innate immunity through recognition of LPS. However, the impact of TLR4 signaling on the development of sepsis-induced immune dysfunction remains unclear. The aim of this study was to investigate the effect of TLR4 on regulatory T cells (Tregs) and its potential mechanism. To simulate sepsis, male C57BL/6 (wild-type) and C57BL/10ScNJNJU (TLR4-/-) mice were subjected to cecal ligation and puncture (CLP). After 24h, pro- and anti-inflammatory cytokine secretion, neutrophil and macrophage lung and liver infiltration were assessed to evaluate the sepsis-induced inflammatory response. The quantity and apoptotic rate of Tregs were measured. The expression of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and forkhead/winged helix transcription factor p3 (Foxp3) were analyzed. Cytokine (i.e., TNF-α, IL-2, IL-10, and IL-4) secretion by Tregs in the cell suspensions and the suppressive activity on CD4+CD25- T cell proliferation were also determined in vitro. At 24h after the CLP procedure, the wild-type mice exhibited increased Treg levels and expression, and secreted inflammatory factors in the serum were markedly overproduced. However, the TLR4-/- mice attenuated the increased Treg expression and inflammatory factor overproduction. These results indicate that in a model of post-septic mice, TLR4 deficiency improves immune paralysis by attenuating Treg activity and restoring a pro-inflammatory cytokine balance. Thus, modulation of the TLR4 activity may be useful in preventing immune dysfunction in sepsis.
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