Toll-like receptor 4 deficiency increases resistance in sepsis-induced immune dysfunction.

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 CD4CD25 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.