2022
DOI: 10.3389/fmolb.2022.1015210
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Water-soluble trehalose glycolipids show superior Mincle binding and signaling but impaired phagocytosis and IL-1β production

Abstract: The tremendous potential of trehalose glycolipids as vaccine adjuvants has incentivized the study of how the structures of these ligands relate to their Mincle-mediated agonist activities. Despite this, structure-activity work in the field has been largely empirical, and less is known about how Mincle-independent pathways might be affected by different trehalose glycolipids, and whether Mincle binding by itself can serve as a proxy for adjuvanticity. There is also much demand for more water-soluble Mincle liga… Show more

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Cited by 6 publications
(7 citation statements)
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“…IL-1β, IL-6, and IL-23 were measured as these cytokines are released by BMDMs in response to PAMP binding to Mincle and/or NOD2 and downstream NF- k B activation and are also required for the complete and sustained development of Th17 cells. , The agonist activity of Mincle ligands is often determined with ligand-coated plates; ,, however, when using this approach, conjugates ( 4 ) and ( 5 ) did not lead to the production of IL-1β or IL-6 by BMDMs, while Mincle agonists C18Brar ( 1 ) and C18Brar-dilipid ( 20 ) led to significant levels of IL-1β or IL-6 by BMDMs (data not shown). Since glycolipid presentation can influence the immunomodulatory properties of Mincle ligands through mechanisms that are not well understood, ,, we assessed the activity of the brartemicin conjugates using a ‘solubilized’ BMDM assay. , …”
Section: Resultsmentioning
confidence: 99%
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“…IL-1β, IL-6, and IL-23 were measured as these cytokines are released by BMDMs in response to PAMP binding to Mincle and/or NOD2 and downstream NF- k B activation and are also required for the complete and sustained development of Th17 cells. , The agonist activity of Mincle ligands is often determined with ligand-coated plates; ,, however, when using this approach, conjugates ( 4 ) and ( 5 ) did not lead to the production of IL-1β or IL-6 by BMDMs, while Mincle agonists C18Brar ( 1 ) and C18Brar-dilipid ( 20 ) led to significant levels of IL-1β or IL-6 by BMDMs (data not shown). Since glycolipid presentation can influence the immunomodulatory properties of Mincle ligands through mechanisms that are not well understood, ,, we assessed the activity of the brartemicin conjugates using a ‘solubilized’ BMDM assay. , …”
Section: Resultsmentioning
confidence: 99%
“…38,54 The agonist activity of Mincle ligands is often determined with ligand-coated plates; 22,32,33 however, when using this approach, conjugates (4) and ( 5) did not lead to the production of IL-1β or IL-6 by BMDMs, while Mincle agonists C18Brar (1) and C18Brardilipid (20) led to significant levels of IL-1β or IL-6 by BMDMs (data not shown). Since glycolipid presentation can influence the immunomodulatory properties of Mincle ligands through mechanisms that are not well understood, 42,55,56 we assessed the activity of the brartemicin conjugates using a 'solubilized' BMDM assay. 50,55 To this end, C18Brar (1), C18Brar-dilipid (20), MDP (3), MDP-C18Brar (4), and MDP-C18Brar-dilipid (5), along with coadministered C18Brar (1) + MDP (3) and C18Brar-dilipid (20) + MDP (3), were added to BMDMs, and the levels of IL-1β, IL-6, and IL-23 were measured by ELISA at 48 h (Figure 5).…”
Section: ■ Resultsmentioning
confidence: 99%
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“…Evidence for this type of effect has been seen in the PEG trehalolipids, as well as the sulfonamide Brartemicin analogs, which did not signal through Mincle or produce cytokines (except at high levels) whereas the less polar amide analogs did. 20,37 To gain further insight into the mode of binding of 1c to Mincle, molecular docking of this compound was undertaken using the Schrodinger software suite. 38 As observed for other trehalose diesters, the trehalose core of 1c bound to the Ca 2+ ion and the EPN motif in the CRD of hMincle, 16,39 while lipid chains occupied adjacent hydrophobic binding grooves (Leu-176/Phe198 and Val167/Ser186; Figure 4).…”
mentioning
confidence: 99%
“…This suggests the polarity imparted by the triazole groups in 1a and 1b diminishes the immune response, whereas the disubstituted compounds are sufficiently hydrophobic to retain Mincle activity such that the production of inflammatory cytokines is observed. Evidence for this type of effect has been seen in the PEG trehalolipids, as well as the sulfonamide Brartemicin analogs, which did not signal through Mincle or produce cytokines (except at high levels) whereas the less polar amide analogs did. , …”
mentioning
confidence: 99%