Below the surface: The inner lives of TLR4 and TLR9

Abstract

TLRs are a class of pattern recognition receptors (PRRs) that detect invading microbes by recognizing pathogen-associated molecular patterns (PAMPs). Upon PAMP engagement, TLRs activate a signaling cascade that leads to the production of inflammatory mediators. The localization of TLRs, either on the plasma membrane or in the endolysosomal compartment, has been considered to be a fundamental aspect to determine to which ligands the receptors bind, and which transduction pathways are induced. However, new observations have challenged this view by identifying complex trafficking events that occur upon TLR-ligand binding. These findings have highlighted the central role that endocytosis and receptor trafficking play in the regulation of the innate immune response. Here, we review the TLR4 and TLR9 transduction pathways and the importance of their different subcellular localization during the inflammatory response. Finally, we discuss the implications of TLR9 subcellular localization in autoimmunity.

Dietary supplementation with spray-dried porcine plasma has prebiotic effects on gut microbiota in mice

“…The kind of response (either pro-or anti-inflammatory) further depends on TLR compartmentalization in the cell. For example, Tlr4 expressed on the cellular membranes plays a pro-inflammatory signaling role involving MyD88 co-activation; 69 while intracellular Tlr4 plays an anti-inflammatory role, inducing the expression of Il-10 70 . Tlr9 activation induces conventional dendritic cells to secrete anti-inflammatory Il-10, thus attenuating inflammatory responses and liver injury in mice 71 .…”

The role of toll like receptor 9 in maintaining gut homeostasis

“…Human TLR9 is limited to plasmacytoid Dendritic Cells (pDCs), neutrophils, B cells and the epithelium whilst mice share the same cellular expression pattern with the addition of macrophages and myeloid Dendritic Cells (mDCs) [2,6]. Within non-polarized cells such as dendritic cells, the endosomal traffi cking system dictates the localization of TLR9 and its resultant signaling cascade [7]. Within these cell types, TLR9 engagement can result in one of two outcomes: either Interferon-Regulatory Factor (IRF)-mediated type 1 interferon or NF B-mediated proinfl ammatory signaling [7].…”

“…Within non-polarized cells such as dendritic cells, the endosomal traffi cking system dictates the localization of TLR9 and its resultant signaling cascade [7]. Within these cell types, TLR9 engagement can result in one of two outcomes: either Interferon-Regulatory Factor (IRF)-mediated type 1 interferon or NF B-mediated proinfl ammatory signaling [7]. Current studies are still examining the mechanisms by which this bifurcated pathway is regulated and the chaperone proteins involved in localizing TLR9 to specifi c endosomal subtypes [8].…”

The Potential of Telomeric G-Quadruplexes Containing Modified Oligoguanosine Overhangs in Activation of Bacterial Phagocytosis and Leukotriene Synthesis in Human Neutrophils

“…Studying the effects of synthetic small molecules on human polymorphonuclear leukocytes (PMNLs or neutrophils) via cellular receptors is currently considered as a promising approach for both the regulation of cellular functions and developing new antibacterial drugs. Toll-like receptors (TLRs) are known to recognize microbes by sensing pathogen-associated molecular patterns (PAMPs) [1] and initiate signaling ways leading to inflammatory response [1,2]. Recently, particular attention has been paid to TLR ligands, which have a modulating effect on innate immunity and are therefore promising The spectrum of possibilities for therapeutic use of TLR9 oligonucleotide ligands is expanding, since expression of this receptor is a prognostic criterion for viral diseases leading to immunosuppression [13,14].…”

“…The biological activity of CpG-ODNs and putative ways for its directed regulation by inhibitory G-rich ODNs are shown schematically in Scheme 1.Biomolecules 2020, 10, x FOR PEER REVIEW 2 of 21 both the regulation of cellular functions and developing new antibacterial drugs. Toll-like receptors (TLRs) are known to recognize microbes by sensing pathogen-associated molecular patterns (PAMPs) [1] and initiate signaling ways leading to inflammatory response [1,2]. Recently, particular attention has been paid to TLR ligands, which have a modulating effect on innate immunity and are therefore promising agents for prevention and treatment of infectious diseases.…”