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Cited by 1,420Immune Response and InflammationCellular transport and secretionInflammasome and immune disorders

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

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Ciesielska, Anna, Matyjek, Marta, Kwiatkowska, Katarzyna·2021·Cellular and Molecular Life Sciences
DOI 10.1007/s00018-020-03656-yPMC PMC7904555
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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.

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  • These bacterial molecules activate toll-like receptors, driving chronic low-grade inflammation.

    “These molecules activate toll-like receptors (TLRs), driving chronic low-grade inflammation [126].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [126]

    The Introduction states that low doses of LPS from gut microbiota can, under certain conditions, enter the bloodstream and cause chronic low-grade TLR4-dependent inflammation. This supports the claim for LPS and TLR4, but not for bacterial molecules and TLRs generally. (LLM, conf=0.85)

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Sorted by citations

Authors
Ciesielska, A., Matyjek, M., & Kwiatkowska, K.
Affiliations
Instytut Biologii Doświadczalnej im. Marcelego Nenckiego (PL)
Corresponding author
Ciesielska, Anna
ORCID
Venue
Cellular and Molecular Life Sciences
Publisher
Springer Science and Business Media LLC
Published
2020-10-15
Volume
78
Issue
4
Pages
1233-1261
ISSN
  • 1420-682X (ISSN-L)
  • 1420-9071
DOI
10.1007/s00018-020-03656-y
PMC
PMC7904555
OpenAlex
W3092750669
Cited by
1,420
References
16
Citations by year
2026: 225 · 2025: 362 · 2024: 328 · 2023: 249 · 2022: 176 · 2021: 80
FWCI
12.59
Type
journal article
Language
en
Open access
Licence
Locations
  • Cellular and Molecular Life Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Narodowe Centrum Nauki (2016/23/D/NZ3/02212)
  • Nencki Institute of Experimental Biology PAS
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Keywords
TLR4, CD14, lipopolysaccharide, endocytosis, receptor trafficking, endosomes, lysosomal degradation, TRIF signaling, MyD88 signaling, TIRAP, tram, endosomal maturation, recycling endosomes, pro-inflammatory signaling, endotoxemia, neurodegeneration, autoimmune disease, cancer
MeSH terms
Humans, Inflammation, Lipopolysaccharides, Membrane Glycoproteins, Phagocytosis, Receptors, Interleukin-1, Lipopolysaccharide Receptors, Adaptor Proteins, Vesicular Transport, Adaptor Proteins, Signal Transducing, Toll-Like Receptor 4, Myeloid Differentiation Factor 88

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