CD14 Is a pattern recognition receptor

Pugin, Jérôme; Heumann, I D; Tomasz, Alexander; Kravchenko, Vladimir V.; Akamatsu, Yuzuru; Nishijima, Masahiro; Glauser, M. P.; Tobias, Peter S.; Ulevitch, Richard J.

doi:10.1016/1074-7613(94)90093-0

Cited by 650 publications

(477 citation statements)

References 34 publications

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“…6B), and the increased production was strongly inhibited by Tm-Gp. These cells have also been shown to express membrane CD14 [35]. Doublestranded viral RNA and bacterial CpG DNA were recently demonstrated to induce cell activation through TLR3 and TLR9, respectively [36,37].…”

Section: Inhibitory Effect Of Tm-gp On Cell Activation Induced By Varmentioning

confidence: 99%

Treponemal glycoconjugate inhibits Toll‐like receptor ligand‐induced cell activation by blocking LPS‐binding protein and CD14 functions

2003

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Spirochetes are well-known as causative agents of various chronic infectious diseases. Glycolipids of small-sized Treponema spirochetes have been shown to exhibit immunostimulating activities. In this study, we found that a glycoconjugate preparation obtained from Treponema medium (Tm-Gp), an intermediate-sized oral Treponema seen in subgingival plaque from patients with chronic periodontal diseases, diminished the LPS-induced activation of a human monocytic cell line, while TNF- § -induced activation was unaffected. NF-‹ B activation in Ba/F3 cells expressing murine Toll-like receptor (TLR) 4 and MD-2 was inhibited by Tm-Gp in a CD14/LPS-binding protein (LBP)-dependent manner when stimulated with LPS or its active center lipid A but not when stimulated with Taxol. Tm-Gp blocked the binding of LPS to immobilized CD14 and LBP and inhibited nitric oxide (NO) production by a murine M ¤ cell line following stimulation with peptidoglycan and LPS in the presence of FBS, while NO production in response poly (I:C) RNA or CpG DNA remained unaffected. The inhibitory effects of Tm-Gp seem to be attributable to the lipophilic portion of the glycoconjugate. These results indicate that T. medium contains a glycoconjugate possessing an inhibitory effect on TLR-mediated cell activation through interaction with LBP and CD14.

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Section: Inhibitory Effect Of Tm-gp On Cell Activation Induced By Varmentioning

confidence: 99%

Treponemal glycoconjugate inhibits Toll‐like receptor ligand‐induced cell activation by blocking LPS‐binding protein and CD14 functions

2003

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“…Although the exact mechanisms of immune activation in pneumococcal meningitis are unknown, recent in vitro experiments provide a clue. The first step in immune activation is thought to be the binding of the pathogen associated molecular pattern (6) peptidoglycan and/or lipoteichoic acid to the pattern recognition receptor membrane CD14 (mCD14) (7)(8)(9). However, mCD14 by itself cannot transmit the activating signal into the cell due to the lack of a transmembrane domain connecting the extracellular domain to the cytoplasm (10).…”

Section: B Acterial Meningitis Caused By Streptococcus Pneumoniaementioning

confidence: 99%

Toll-Like Receptor 2 Participates in Mediation of Immune Response in Experimental Pneumococcal Meningitis

Koedel¹,

Angele²,

Rupprecht³

et al. 2003

The Journal of Immunology

206

173

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Heterologous expression of Toll-like receptor (TLR)2 and CD14 in Chinese hamster ovary fibroblasts was reported to confer responsiveness to pneumococcal peptidoglycan. The present study characterized the role of TLR2 in the host immune response and clinical course of pneumococcal meningitis. Pneumococcal infection of mice caused a significant increase in brain TLR2 mRNA expression at both 4 and 24 h postchallenge. Mice with a targeted disruption of the TLR2 gene (TLR2−/−) showed a moderate increase in disease severity, as evidenced by an aggravation of meningitis-induced intracranial complications, a more pronounced reduction in body weight and temperature, and a deterioration of motor impairment. These symptoms were associated with significantly higher cerebellar and blood bacterial titers. Brain expression of the complement inhibitor complement receptor-related protein y was significantly higher in infected TLR2−/− than in wild-type mice, while the expression of the meningitis-relevant inflammatory mediators IL-1β, TNF-α, IL-6, macrophage-inflammatory protein (MIP)-2, inducible NO synthase, and C3 was similar in both genotypes. We first ectopically expressed single candidate receptors in HEK293 cells and then applied peritoneal macrophages from mice lacking TLR2 and/or functional TLR4 for further analysis. Overexpression of TLR2 and TLR4/MD-2 conferred activation of NF-κB in response to pneumococcal exposure. However, pneumococci-induced TNF-α release from peritoneal macrophages of wild-type and TLR2/functional TLR4/double-deficient mice did not differ. Thus, while TLR2 plays a significant role in vivo, yet undefined pattern recognition receptors contribute to the recognition of and initiation of the host immune defense toward Streptococcus pneumoniae infection.

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“…To date, several studies have confirmed interactions of CD14 with a variety of microbial ligands such as lipopolysaccaride (LPS) from gram-negative bacteria, lipoteichoic acid (LTA) and peptidoglycan (PGN) from gram-positive bacteria, lipoproteins, lipoarabinomannan, polymannuronic acids and even with synthetic molecules [1,[5][6][7][8][9]. The ability of CD14 to interact with such structurally diverse endotoxins has led to the hypothesis that CD14 functions as a pattern recognition receptor by recognizing and binding to different pathogen-associated molecular patterns [7].…”

mentioning

confidence: 99%

“…The ability of CD14 to interact with such structurally diverse endotoxins has led to the hypothesis that CD14 functions as a pattern recognition receptor by recognizing and binding to different pathogen-associated molecular patterns [7]. It is believed that this pattern recognition may be important for high selectivity of CD14-mediated cellular activation and distinctiveness of the signaling pathway in response to specific ligands [10].…”

mentioning

confidence: 99%

Solution NMR studies provide structural basis for endotoxin pattern recognition by the innate immune receptor CD14

Albright¹,

Chen²,

Holbrook³

et al. 2008

Biochemical and Biophysical Research Communications

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CD14 functions as a key pattern recognition receptor for a diverse array of gram-negative and grampositive cell-wall components in the host innate immune response by binding to pathogen-associated molecular patterns (PAMPs) at partially overlapping binding site(s). To determine the potential contribution of CD14 residues in this pattern recognition, we have examined using solution NMR spectroscopy the binding of three different endotoxin ligands, Lipopolysaccharide, lipoteichoic acid and a PGN-derived compound, muramyl dipeptide to a 15 N isotopically labeled 152-residue Nterminal fragment of sCD14 expressed in Pichia pastoris. Mapping of NMR spectral changes upon addition of ligands revealed that the pattern of residues affected by binding of each ligand is partially similar and partially different. This first direct structural observation of the ability of specific residue combinations of CD14 to differentially affect endotoxin binding may help explain the broad specificity of CD14 in ligand recognition and provide a structural basis for pattern recognition. Another interesting finding from the observed spectral changes is that the mode of binding may be dynamically modulated and could provide a mechanism for binding endotoxins with structural diversity through a common binding site. KeywordsNMR; human CD14 structure; CD14-endotoxin complex; endotoxin; pattern recognition; pichia pastoris expression; isotopic labeling; cell-based assay; lipopolysaccharide; ReLPS; LTA; BODIPY Clinical manifestation of sepsis typically involves a complex interaction between the host immune system and major bacterial cell wall constituents known as endotoxins. The cluster differentiation antigen, CD14, has been shown to be a key high-affinity cellular receptor for these bacterial endotoxins and plays an important role in endotoxin-induced activation of innate immune cells [1]. In humans, CD14 is constitutively expressed on cell surfaces of monocytes/ macrophages as a 55 kDa membrane-bound protein and also exists in a soluble form (sCD14), in serum and bodily fluids in concentrations of 2-6 μg/ml [2,3]. Recognition and binding of different microbial endotoxins to both mCD14 and sCD14 initiates a signaling cascade mediated by Toll-like receptors (TLRs) that promotes the synthesis and secretion of multiple host-derived inflammatory mediators [4], overactivation of which is ultimately responsible for the deleterious effects of sepsis. Understanding mechanism of endotoxin recognition is

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CD14 Is a pattern recognition receptor

Cited by 650 publications

References 34 publications

Treponemal glycoconjugate inhibits Toll‐like receptor ligand‐induced cell activation by blocking LPS‐binding protein and CD14 functions

Treponemal glycoconjugate inhibits Toll‐like receptor ligand‐induced cell activation by blocking LPS‐binding protein and CD14 functions

Toll-Like Receptor 2 Participates in Mediation of Immune Response in Experimental Pneumococcal Meningitis

Solution NMR studies provide structural basis for endotoxin pattern recognition by the innate immune receptor CD14

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