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

Autor:	Manthrirathna MATP; School of Chemical and Physical Sciences, Victoria University of Wellington, Wellington, New Zealand., Dangerfield EM; School of Chemical and Physical Sciences, Victoria University of Wellington, Wellington, New Zealand.; Centre for Biodiscovery, Victoria University of Wellington, Wellington, New Zealand., Ishizuka S; Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.; Laboratory of Molecular Immunology, Immunology Frontier Research Center, Osaka University, Osaka, Japan., Woods A; School of Chemical and Physical Sciences, Victoria University of Wellington, Wellington, New Zealand., Luong BS; School of Chemical and Physical Sciences, Victoria University of Wellington, Wellington, New Zealand.; Centre for Biodiscovery, Victoria University of Wellington, Wellington, New Zealand., Yamasaki S; Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.; Laboratory of Molecular Immunology, Immunology Frontier Research Center, Osaka University, Osaka, Japan.; Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.; Division of Molecular Immunology, Medical Mycology Research Center, Chiba University, Chiba, Japan., Timmer MSM; School of Chemical and Physical Sciences, Victoria University of Wellington, Wellington, New Zealand.; Centre for Biodiscovery, Victoria University of Wellington, Wellington, New Zealand., Stocker BL; School of Chemical and Physical Sciences, Victoria University of Wellington, Wellington, New Zealand.; Centre for Biodiscovery, Victoria University of Wellington, Wellington, New Zealand.
Jazyk:	angličtina
Zdroj:	Frontiers in molecular biosciences [Front Mol Biosci] 2022 Nov 24; Vol. 9, pp. 1015210. Date of Electronic Publication: 2022 Nov 24 (Print Publication: 2022).
DOI:	10.3389/fmolb.2022.1015210
Abstrakt:	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. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Manthrirathna, Dangerfield, Ishizuka, Woods, Luong, Yamasaki, Timmer and Stocker.)
Databáze:	MEDLINE
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