TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling

Abstract

Toll-like receptor (TLR) 4 belongs to the TLR family of receptors inducing pro-inflammatory responses to invading pathogens. TLR4 is activated by lipopolysaccharide (LPS, endotoxin) of Gram-negative bacteria and sequentially triggers two signaling cascades: the first one involving TIRAP and MyD88 adaptor proteins is induced in the plasma membrane, whereas the second engaging adaptor proteins TRAM and TRIF begins in early endosomes after endocytosis of the receptor. The LPS-induced internalization of TLR4 and hence also the activation of the TRIF-dependent pathway is governed by a GPI-anchored protein, CD14. The endocytosis of TLR4 terminates the MyD88-dependent signaling, while the following endosome maturation and lysosomal degradation of TLR4 determine the duration and magnitude of the TRIF-dependent one. Alternatively, TLR4 may return to the plasma membrane, which process is still poorly understood. Therefore, the course of the LPS-induced pro-inflammatory responses depends strictly on the rates of TLR4 endocytosis and trafficking through the endo-lysosomal compartment. Notably, prolonged activation of TLR4 is linked with several hereditary human diseases, neurodegeneration and also with autoimmune diseases and cancer. Recent studies have provided ample data on the role of diverse proteins regulating the functions of early, late, and recycling endosomes in the TLR4-induced inflammation caused by LPS or phagocytosis of E. coli. In this review, we focus on the mechanisms of the internalization and intracellular trafficking of TLR4 and CD14, and also of LPS, in immune cells and discuss how dysregulation of the endo-lysosomal compartment contributes to the development of diverse human diseases.

MNK as a potential pharmacological target for suppressing LPS-induced acute lung injury in mice

“…Toll-like receptor 4 (TLR4) is a transmembrane protein encoded by the TLR4 gene, which is involved in the innate immune response [16] , [17] , [18] . A number of studies have shown that LPS is the ligand of TLR4 and stimulates the inflammatory response of the lungs by binding to TLR4 [19] , [20] , [21] , [22] . It is now verified that TLR4-mediated mitogen-activated protein kinases (MAPKs) signaling pathways are responsible for the production of a variety of pro-inflammatory cytokines [23] , [24] , [25] , [26] .…”

Epigenomic and transcriptomic differences between low-grade and acute inflammation in LPS-induced murine immune cells

“…For example, enhancers who had much higher signal in Low-dose were linked to genes like Csf1, Irf5, Rab11a, Ccr5, Irf7, Ticam2, Ifit3, and Irf1, while enhancers with lower signal in Low-dose were linked to genes like Arg1, Hdac5, and Treml1. Rab11a is responsible for transporting TLR4 from the endocytic recycling compartment to forming phagosomes 37 . This transport triggers the TRIF-dependent signalling pathway, which requires TRAM (Ticam2).…”

“…Finally, both pathways are involved in the canonical activation of the NRLP3 inflammasome, which is responsible for the activation of the inflammatory cytokine, IL-1β, and can cause pyroptosis, a form of programmed cell-death 37 .…”

“…The copyright holder for this preprint this version posted March 29, 2021. ; https://doi.org/10.1101/2021.03.28.437377 doi: bioRxiv preprint of LPS-dosage on the epigenome and, in turn, the transcriptome of immune cells. Furthermore, we also analyzed the effects of TRAM deletion, necessary for the TRIFdependent pathway 37 , and IRAK-M deletion, which suppresses TLR-signaling and is associated with endotoxin tolerance 57 . Altogether, this analysis could help elucidate the means by which subclinical concentrations of endotoxin can lead to low-grade inflammation as opposed to acute inflammation.…”

Transcriptome Analysis of Selenium-Treated Porcine Alveolar Macrophages Against Lipopolysaccharide Infection

“…Several Gram-negative bacteria, including Actinobacillus pleuropneumoniae and Haemophilus parasuis, are responsible for respiratory diseases and cause huge economic losses to the swine industry worldwide. Lipopolysaccharide (LPS) is a cell outer membrane component of Gram-negative bacteria and serves as a major pro-inflammatory stimulus binding to pattern recognition receptor Toll-like receptor 4 (TLR4) (Ciesielska et al, 2020). LPS is ubiquitous in nature and exists in high concentrations in air pollution, soil, and organic dust.…”