TLR4 Signaling Pathway Modulators as Potential Therapeutics in Inflammation and Sepsis

Abstract

Toll-Like Receptor 4 (TLR4) signal pathway plays an important role in initiating the innate immune response and its activation by bacterial endotoxin is responsible for chronic and acute inflammatory disorders that are becoming more and more frequent in developed countries. Modulation of the TLR4 pathway is a potential strategy to specifically target these pathologies. Among the diseases caused by TLR4 abnormal activation by bacterial endotoxin, sepsis is the most dangerous one because it is a life-threatening acute system inflammatory condition that still lacks specific pharmacological treatment. Here, we review molecules at a preclinical or clinical phase of development, that are active in inhibiting the TLR4-MyD88 and TLR4-TRIF pathways in animal models. These are low-molecular weight compounds of natural and synthetic origin that can be considered leads for drug development. The results of in vivo studies in the sepsis model and the mechanisms of action of drug leads are presented and critically discussed, evidencing the differences in treatment results from rodents to humans.

TRAF3-interacting JNK-activating modulator promotes inflammation by stimulating translocation of Toll-like receptor 4 to lipid rafts

“…relayed from the membrane proximity toward the downstream area (6,24). To test this possibility, we performed endogenous immunoprecipitation (IP) and immunoblotting assays in THP-1-derived macrophages using an antibody against T3JAM.…”

Narciclasine improves outcome in sepsis among neonatal rats via inhibition of calprotectin and alleviating inflammatory responses

“…The pathogenesis of sepsis involves the dysregulated activation of inflammatory mediator networks which results in the hyper-production of inflammatory cytokines. The toll like receptor 4 (TLR-4) pathway is activated by bacterial LPS which is the major component of the cell wall of gram negative bacteria 29 . This subsequently triggers an intracellular signaling cascade that ultimately results in the secretion of inflammatory cytokines.…”

“…This subsequently triggers an intracellular signaling cascade that ultimately results in the secretion of inflammatory cytokines. The intracellular and extracellular components of the TLR4 signaling cascade are potential therapeutic targets for the treatment of acute inflammation disorders like sepsis where there is excessive cytokine secretion 29 . The NF-kappa B activation is a central event in the activation of these crucial networks 32 .…”

“…Narciclasine inhibited the expression of adaptor proteins of the TLR4 pathway, reduced Iκβα degradation and nf-κβ p65 phosphorylation in livers of neonatal rats with sepsis. The toll like receptor 4 (TLR-4) pathway has a crucial role in triggering the innate immune response in acute inflammation associated disorders like sepsis 29 . It is activated by bacterial endotoxins which triggers the downstream signaling cascade that results in the production of inflammatory cytokines.…”

The Protective Effect of Germanium Citrate on Functional State of Immune Cells and Neutrophil Activity Under the Condition of Lipolysaccharide Induced Inflammation

“…Зазначені зміни можуть бути пов'язані з тим, що ліпополісахарид є лігандом рецепторів TLR-4, які експресуються переважно на клітинах імунної системи і є важливим компонентом захисту організму від бактеріальних інфекцій. Результатом взаємодії TLR-4 з ліпополісахаридом є, зокрема, активація клітин неспецифічної резистентності, що призводить до посилення їх бактерицидності та видаленню бактерій [16].…”