Soluble CD14 Discriminates Slight Structural Differences between Lipid As That Lead to Distinct Host Cell Activation

Asai, Yasuyuki; Makimura, Yutaka; Kawabata, Atsushi; Ogawa, Tomohiko

doi:10.4049/jimmunol.179.11.7674

Cited by 28 publications

(21 citation statements)

References 67 publications

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“…If true, the absence of CD14 could not only contribute to the well-known hyporesponsiveness of fish cells to Gram-negative (26,79) bacteria but also to the hyporesponsiveness of fish cells to ligands from Gram-positive bacteria reported in this study.…”

Section: Ros Production Modulates Tlr2 Gene Expressionmentioning

confidence: 74%

Evolution of Recognition of Ligands from Gram-Positive Bacteria: Similarities and Differences in the TLR2-Mediated Response between Mammalian Vertebrates and Teleost Fish

Ribeiro

Hermsen

Taverne-Thiele

et al. 2010

The Journal of Immunology

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We investigated the role of the TLR2 receptor in the recognition of ligands from Gram-positive bacteria in fish. Comparative sequence analysis showed a highly conserved Toll/IL-1 receptor domain. Although the leucine-rich repeat domain was less conserved, the position of the critical peptidoglycan (PGN)-binding residues in the leucine-rich repeat domain of carp TLR2 were conserved. Transfection of human embryonic kidney 293 cells with TLR2 corroborated the ability of carp TLR2 to bind the prototypical mammalian vertebrate TLR2 ligands lipoteichoic acid (LTA) and PGN from Staphylococcus aureus. The synthethic triacylated lipopeptide N-palmitoyl-S-(2,3-bis(palmitoyloxy)-(2RS)-propyl)-(R)-Cys-(S)-Ser-(S)-Lys4 trihydrochloride (Pam3CSK4) but not the diacylated lipopeptide macrophage-activating lipopeptide-2 (MALP-2) also activated TLR2 transfected human cells. We identified clear differences between the mammalian vertebrates and carp TLR2-mediated response. The use of the same ligands on carp macrophages indicated that fish cells require high concentrations of ligands from Gram-positive bacteria (LTA, PGN) for activation and signal transduction, react less strongly (Pam3CSK4) or do not react at all (MALP-2). Overexpression of TLR2 in carp macrophages confirmed TLR2 reactivity of the response to LTA and PGN, low-responsiveness to Pam3CSK4 and nonresponsiveness to MALP-2. A putative relation with the apparent absence of accessory proteins such as CD14 from the fish TLR2-containing receptor complex is discussed. Moreover, activation of carp macrophages by PGN resulted in increased TLR2 gene expression and enhanced TLR2 mRNA stability, MAPK-p38 phosphorylation and increased radical production. Finally, we could show that NADPH oxidase-derived radicals and MAPK-p38 activation cooperatively determine the level of PGN-induced TLR2 gene expression. We propose that the H2O2-MAPK-p38–dependent axis is crucial for regulation of TLR2 gene expression in fish macrophages.

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Section: Ros Production Modulates Tlr2 Gene Expressionmentioning

confidence: 74%

Evolution of Recognition of Ligands from Gram-Positive Bacteria: Similarities and Differences in the TLR2-Mediated Response between Mammalian Vertebrates and Teleost Fish

Ribeiro

Hermsen

Taverne-Thiele

et al. 2010

The Journal of Immunology

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“…In general, lipid A with a reduced number of acyl chains can serve as an inhibitor of immune activation induced by G Ϫ bacteria (19). A previous study revealed that lipid A from F. nucleatum is a hexaacylated fatty acid composed of tetradecanoate (C 14 ) and hexadecanoate (C 16 ) and is structurally similar to Escherichia coli synthetic lipid A (20). This may be an explanation for the strong TLR4 activity of F. nucleatum In contrast, the structure of P. gingivalis lipid A is different from that of E. coli.…”

Section: Discussionmentioning

confidence: 99%

Diverse Toll-Like Receptors Mediate Cytokine Production by Fusobacterium nucleatum and Aggregatibacter actinomycetemcomitans in Macrophages

et al. 2014

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“…The role of sCD14 in the activation of the TRIF/IRF3 pathway was previously studied by Beutler who demonstrated that CD14 molecule was required for TRIF pathway [8]. Moreover Ogawa and colleagues suggested a discriminative role of sCD14 for slight differences in the structure of TLR4 agonists [10]. CRX-527 activity is clearly maintained in the absence of CD14.…”

Section: Resultsmentioning

confidence: 97%

“…Cells which express TLR4 but not mCD14, such as endothelial cells and monocytederived DC (MoDC), can use the soluble form of CD14 (sCD14) to mount TLR4-mediated responses to LPS [9]. sCD14 was recently shown to discriminate slight structural differences between distinct TLR4 ligands [10]. The present study was therefore undertaken to determine whether or not mCD14 or sCD14 impacts the TLR4 agonist activity of CRX-527.…”

Section: Introductionmentioning

confidence: 99%

CD14‐independent responses induced by a synthetic lipid A mimetic

et al. 2010

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CRX-527 belongs to a new family of synthetic lipid A mimetics, the aminoalkyl glucosaminide 4-phosphates, which are considered as potential vaccine adjuvants or standalone immunotherapeutics to harness innate immune defenses. Since natural lipid A from bacterial LPS depends on membrane-bound (mCD14) or soluble CD14 for its TLR4 ligand activity, we investigated the involvement of both forms of CD14 in the responses elicited by CRX-527. First, we found that CRX-527 induces NF-jB and interferon regulatory factor-3 (IRF-3) activation in human embryonic kidney cells transfected with TLR4 and MD-2 genes alone, whereas the responses to LPS require either co-transfection of the gene encoding mCD14 or addition of soluble CD14. We then observed that monocyte-derived DC, which are devoid of mCD14 respond to CRX-527 but not to LPS in serum-free medium. Furthermore, we found that, in contrast to LPS, CRX-527 induces the production of cytokines in whole blood of a patient with paroxysmal nocturnal hemoglobinuria, a disease in which mCD14-dependent responses are defective. Finally, we demonstrated that splenocytes from CD14-deficient mice produce cytokines in response to CRX-527 but not to LPS. We conclude that the lipid A mimetic CRX-527 does not require the CD14 co-receptor to elicit TLR4-mediated responses.Key words: CD14 . Lipid A . TLR4 Supporting Information available online IntroductionAminoalkyl glucosaminide phosphates lipid A mimetics are currently developed as synthetic Toll-like receptor 4 (TLR4) agonists with possible applications as vaccine adjuvants or standalone immunostimulants [1][2][3][4]. The hexa-acylate compound CRX-527, composed of three myristic and three decanoic acyl chains, has been described as one of the most powerful members of this aminoalkyl glucosaminide 4-phosphate family [5]. CD14, a GPI-anchored protein expressed at the surface of phagocytes, has been shown to be involved in the induction of TLR4-mediated responses by bacterial LPS [6,7]. Indeed, LPS was shown to bind the LPS binding protein facilitating its transfer to membranebound CD14 (mCD14), which allows LPS to engage TLR4 associated with MD-2 [6]. There is evidence that CD14 is especially important for TLR4 response mediated by the TRIF adaptor molecule, which culminates in activation of the transcription factor interferon regulatory factor-3 (IRF3) required for the production of type I interferon [8]. Cells which express TLR4 but not mCD14, such as endothelial cells and monocytederived DC (MoDC), can use the soluble form of CD14 (sCD14) to mount TLR4-mediated responses to LPS [9]. sCD14 was recently shown to discriminate slight structural differences between distinct TLR4 ligands [10]. The present study was therefore SHORT COMMUNICATION Results and discussionExpression of TLR4 and MD-2 is sufficient for the induction of NF-jB and IRF3 activities by CRX-527In preliminary experiments using transfected human embryonic kidney (HEK) cells expressing different TLR receptors, we confirmed that CRX-527 is a TLR4 agonist devoid of activity o...

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Soluble CD14 Discriminates Slight Structural Differences between Lipid As That Lead to Distinct Host Cell Activation

Cited by 28 publications

References 67 publications

Evolution of Recognition of Ligands from Gram-Positive Bacteria: Similarities and Differences in the TLR2-Mediated Response between Mammalian Vertebrates and Teleost Fish

Evolution of Recognition of Ligands from Gram-Positive Bacteria: Similarities and Differences in the TLR2-Mediated Response between Mammalian Vertebrates and Teleost Fish

Diverse Toll-Like Receptors Mediate Cytokine Production by Fusobacterium nucleatum and Aggregatibacter actinomycetemcomitans in Macrophages

CD14‐independent responses induced by a synthetic lipid A mimetic

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