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

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.

• Authors: Chao Cao, Yanfen Chai, Songtao Shou, Jun Wang, Ying Huang, Tao Ma
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 54 Pg. 169-176 (Jan 2018) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 29149705 (Publication Type: Journal Article)
• Copyright: Copyright © 2017. Published by Elsevier B.V.

Chemical References

• CTLA-4 Antigen
• Cytokines
• Forkhead Transcription Factors
• Foxp3 protein, mouse
• Lipopolysaccharides
• Toll-Like Receptor 4

Topics

• Animals
• Apoptosis
• CTLA-4 Antigen (genetics, metabolism)
• Cecum (surgery)
• Cytokines (metabolism)
• Disease Models, Animal
• Forkhead Transcription Factors (genetics, metabolism)
• Gene Expression Regulation
• Humans
• Immunity, Innate
• Immunologic Deficiency Syndromes (genetics, immunology)
• Lipopolysaccharides (immunology)
• Lung (immunology)
• Macrophages (immunology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Sepsis (genetics, immunology)
• Signal Transduction
• T-Lymphocytes, Regulatory (immunology)
• Toll-Like Receptor 4 (genetics, metabolism)