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

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 ad...

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Autores principales: Ciesielska, Anna, Matyjek, Marta, Kwiatkowska, Katarzyna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904555/
https://www.ncbi.nlm.nih.gov/pubmed/33057840
http://dx.doi.org/10.1007/s00018-020-03656-y
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author Ciesielska, Anna
Matyjek, Marta
Kwiatkowska, Katarzyna
author_facet Ciesielska, Anna
Matyjek, Marta
Kwiatkowska, Katarzyna
author_sort Ciesielska, Anna
collection PubMed
description 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.
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spelling pubmed-79045552021-03-09 TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling Ciesielska, Anna Matyjek, Marta Kwiatkowska, Katarzyna Cell Mol Life Sci Review 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. Springer International Publishing 2020-10-15 2021 /pmc/articles/PMC7904555/ /pubmed/33057840 http://dx.doi.org/10.1007/s00018-020-03656-y Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Review
Ciesielska, Anna
Matyjek, Marta
Kwiatkowska, Katarzyna
TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling
title TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling
title_full TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling
title_fullStr TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling
title_full_unstemmed TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling
title_short TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling
title_sort tlr4 and cd14 trafficking and its influence on lps-induced pro-inflammatory signaling
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904555/
https://www.ncbi.nlm.nih.gov/pubmed/33057840
http://dx.doi.org/10.1007/s00018-020-03656-y
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