The molecular mechanisms of TLR‐signaling cooperation in cytokine regulation

Abstract

Innate immune cells recognize pathogens through pattern recognition receptors (PRRs), and activation of PRRs induces downstream signaling pathways to mount appropriate immune responses. Pathogens usually carry multiple ligands, which can simultaneously activate multiple PRRs. The cooperation of multiple PRRs and consequential crosstalk between their downstream pathways could enhance cytokine expression, which is required for effective immune responses. On the other hand, immune over-activation could also harm the host if immune homeostasis is not restored. Therefore, it is important to understand the mechanisms of PRR cooperation during an infection. As the best characterized PRRs, Toll-like receptors (TLRs) have an important role in pathogen recognition, and crosstalk among TLRs is common. In this review, we provide an update on the recent findings on the mechanisms of TLR cooperation. We summarize the known mechanisms and provide a future perspective on TLR crosstalk study, with a caution against the use of multiple TLR ligands as adjuvants in therapeutic strategies.

Expression Profiling of Long Noncoding RNA Splice Variants in Human Microvascular Endothelial Cells: Lipopolysaccharide EffectsIn Vitro

“…The innate immune recognition of bacterial products is orchestrated by a family of transmembrane receptors known as Toll-like receptors (TLRs) [17]. Endothelial cells are known to express a number of TLRs, including TLR4, and display an activated phenotype mediated by a receptor complex consisting of TLR4, cluster of differentiation 14 (CD14), and myeloid differentiation protein-2 (MD-2) in response to LPS [1].…”

Adjuvant-Loaded Spiky Gold Nanoparticles for Activation of Innate Immune Cells

“…Our results indicate that these adjuvant-SGNP nano-complexes can promote efficient cellular uptake of pIC and CpG by innate immune cells and mediate co-delivery of multiple adjuvant species to endolysosomal compartments, where TLR3 and TLR9 are expressed, 3–5 in a spatio-temporally controlled manner. In particular, co-localized delivery of dual adjuvants mediated by SGNP nano-complexes induced potent, synergistic immune activation of BMDCs with much lower concentrations of adjuvants than free soluble adjuvants.…”

“…2 Pathogen recognition during infection involves simultaneous or sequential engagement of PRRs on innate immune cells by multiple PAMPs, which activate distinct or shared signaling pathways and induce immune stimulation in a synergistic manner. 3–5 Synthetic molecules mimicking the structures and functions of PAMPs can serve as effective adjuvants for stimulation of the innate immune system. In particular, TLR agonists have been widely investigated as vaccine adjuvants.…”

Toll-Like Receptor-Mediated Free Radical Generation in Clonorchis sinensis Excretory-Secretory Product-Treated Cholangiocarcinoma Cells

“…However, prolonged inflammation resulting from excessive production of inflammatory cytokines and chemokines via TLR-mediated signaling events can be detrimental owing to host toxicity and tissue damage. Thus, while T-helper 1 (Th1)-based inflammatory consequences orchestrated by TLRs are involved in eliminating pathogenic infections, they may also induce fatal pathogenic consequences [8]. Similarly, the pathogen-modulated Th2-based TLR-mediated signaling pathway develops immune responses beneficial for the pathogen, leading to disease progression.…”