TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling
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Cellular and Molecular Life Sciences
REVIEW
TLR4 and CD14 trafficking and its influence on LPS‑induced pro‑inflammatory signaling Anna Ciesielska1 · Marta Matyjek1 · Katarzyna Kwiatkowska1 Received: 10 June 2020 / Revised: 25 August 2020 / Accepted: 22 September 2020 © The Author(s) 2020
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 GPIanchored 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. Keyword CD14 · Endocytosis · Endotoxin · Endosome · LPS · TLR4 Abbreviations AD Alzheimer’s disease ALS Amyotrophic lateral sclerosis AOHA Acyloxyacyl hydrolase Arf6 ADP-ribosylation factor 6 BMDC Bone marrow-derived dendritic cells BMDM Bone marrow-derived macrophages CF Cystic fibrosis CFTR Cystic fibrosis transmembrane conductance regulator CHS Chédiak–Higashi syndrome CLIC Clathrin-independent carrier Dab2 Disabled-2 DAMP Damage-associated molecular pattern * Anna Ciesielska [email protected] 1
Laboratory of Molecular Membrane Biology, Nencki Institute of Experimental Biology of Polish Academy of Sciences, 3 Pasteur St., 02‑093 Warsaw, Poland
DC Dendritic cells ERC Endosomal recycling compartment GAG Glycosaminoglycan GEEC GPI-AP-enriched early endosomal compartment GMFG Glia maturation factor-γ GPI-AP Glycosylphosphatidylinositol-anchored proteins HMGB1 High mobility group box protein 1 IP3 Inositol 1,4,5-trisphosphate IFN Interferon IKK IκB kinase IL Interleukin IRAK Interleukin-1 re
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