The effects of trehalose glycolipid presentation on cytokine production by GM-CSF macrophages

Stocker, Bridget L.; Kodar, Kristel; Wahi, Kanu; Foster, Amy J.; Harper, Jacquie L.; Mori, Daiki; Yamasaki, Satoshi; Timmer, Mattie S. M.

doi:10.1007/s10719-018-09857-9

Cited by 19 publications

(17 citation statements)

References 33 publications

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“…The distinct lack of IL-1β production in response to 4f and the other PEG-TGLs prompted us to consider the mechanism by which 4f and TDB lead to IL-1β production. Although we, and others, had previously determined that glycolipid presentation can influence the immune response to trehalose glycolipids (Kallerup et al, 2017;Stocker et al, 2019), the molecular mechanisms for this were not investigated. Moreover, we had previously observed that short-chain trehalose glycolipids led to a less inflammatory immune response (Khan et al, 2011;Khan et al, 2018), though had assumed that this might be related to poor Mincle binding.…”

Section: Discussionmentioning

confidence: 99%

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Water-soluble trehalose glycolipids show superior Mincle binding and signaling but impaired phagocytosis and IL-1β production

Manthrirathna

Dangerfield

Ishizuka

et al. 2022

Front. Mol. Biosci.

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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 ligands. To address this need, we prepared polyethylene glycol modified trehalose glycolipids (PEG-TGLs) with enhanced water solubility and strong murine Mincle (mMincle) binding and signaling. However, only modest cytokine and chemokine responses were observed upon the treatment of GM-CSF treated bone-marrow cells with the PEG-TGLs. Notability, no IL-1β was observed. Using RNA-Seq analysis and a representative PEG-TGL, we determined that the more water-soluble adducts were less able to activate phagocytic pathways, and hence, failed to induce IL-1β production. Taken together, our data suggests that in addition to strong Mincle binding, which is a pre-requisite for Mincle-mediated cellular responses, the physical presentation of trehalose glycolipids in colloidal form is required for inflammasome activation, and hence, a strong inflammatory immune response.

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Section: Discussionmentioning

confidence: 99%

“…Bone-marrow cells were collected from femurs and tibias of wild type (C57BL/6) or Mincle −/− mice and the cells cultured as previously reported (50 ng/ml of GM-CSF) ( Stocker et al, 2019 ). On day 8, all media together with non-adherent cells were removed and 0.25 ml fresh media was added to each well (48 well plate).…”

Section: Methodsmentioning

confidence: 99%

Water-soluble trehalose glycolipids show superior Mincle binding and signaling but impaired phagocytosis and IL-1β production

Manthrirathna

Dangerfield

Ishizuka

et al. 2022

Front. Mol. Biosci.

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“…These results highlight the importance of using multiple assays to investigate ligand activity. 34 In our studies, no major differences were observed in activity between anomers of the same compound when using mMincle reporter cells and murine BMMs. Furthermore, the addition of a second lipid at the anomeric position of the glucose moiety did not contribute to better ligand activity for mMincle.…”

Section: Organic and Biomolecular Chemistrymentioning

confidence: 47%

“…This latter point is important, for while Mincle signaling provides an indication of agonist activity, it does not always reveal the functional potency of a ligand or the manner in which a ligand skews the immune response. 16,25,33,34…”

Section: Introductionmentioning

confidence: 99%

Lipophilic glucose monoesters and glycosides are potent human Mincle agonists

et al. 2022

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“…[3] Notably, TDB has been applied to a cationic liposomal system CAF01, [8] which was evaluated in human clinical trials against tuberculosis and HIV. [9,10] Various Mincle ligands have been reported including the glycolipids such as 6-acylated glycosides, [11] glucosyl diacylglycerides, [12][13][14] other trehalose esters, [15][16][17][18][19][20][21][22][23][24] and also recently found cholesteryl acyl α-glucosides (αCAG). [25][26][27] We previously reported that 1-monoacylglycerol harbors relationships between activity and acyl chain length.…”

Section: Introductionmentioning

confidence: 99%

Fungal β‐Mannosyloxymannitol Glycolipids and Their Analogues: Synthesis and Mincle‐Mediated Signaling Activity

et al. 2022

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Mincle, a C-type lectin receptor (CLR), senses certain lipid conjugates, leading to the activation of the innate immune system. The lipid conjugate ligands include glyco-, glycero-, and mannitol lipids. Recently, a fungal β-mannosyloxymannitol glycolipid demonstrating a novel architecture, "44-2," was isolated from the fungus Malassezia and displayed potent Mincle-mediated signaling activity. For this study, we synthe-sized the diastereomeric pair of mannosyloxymannitol glycolipids and their analogues and analyzed the structure-activity relationships of Mincle-mediated signaling. The results suggest that the dimannosyl-fatty acid moiety in the mannosyloxymannitol glycolipid-type structure plays a major role in the molecular recognition of Mincle.

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The effects of trehalose glycolipid presentation on cytokine production by GM-CSF macrophages

Cited by 19 publications

References 33 publications

Water-soluble trehalose glycolipids show superior Mincle binding and signaling but impaired phagocytosis and IL-1β production

Water-soluble trehalose glycolipids show superior Mincle binding and signaling but impaired phagocytosis and IL-1β production

Lipophilic glucose monoesters and glycosides are potent human Mincle agonists

Fungal β‐Mannosyloxymannitol Glycolipids and Their Analogues: Synthesis and Mincle‐Mediated Signaling Activity

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