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Aryl-functionalised α,α′-Trehalose 6,6′-Glycolipid Induces Mincle-independent Pyroptotic Cell Death

Authors :
Kristel Kodar
Emma M. Dangerfield
Amy J. Foster
Devlin Forsythe
Shigenari Ishizuka
Melanie J. McConnell
Sho Yamasaki
Mattie S. M. Timmer
Bridget L. Stocker
Source :
Inflammation.
Publication Year :
2023
Publisher :
Springer Science and Business Media LLC, 2023.

Abstract

Abstract—α,α′-Trehalose 6,6′-glycolipids have long been known for their immunostimulatory properties. The adjuvanticity of α,α′-trehalose 6,6′-glycolipids is mediated by signalling through the macrophage inducible C-type lectin (Mincle) and the induction of an inflammatory response. Herein, we present an aryl-functionalised trehalose glycolipid, AF-2, that leads to the release of cytokines and chemokines, including IL-6, MIP-2 and TNF-α, in a Mincle-dependent manner. Furthermore, plate-coated AF-2 also leads to the Mincle-independent production of IL-1β, which is unprecedented for this class of glycolipid. Upon investigation into the mode of action of plate-coated AF-2, it was observed that the treatment of WT and Mincle−/− bone marrow derived macrophages (BMDM), murine RAW264.7 cells, and human monocytes with AF-2 led to lytic cell death, as evidenced using Sytox Green and lactate dehydrogenase assays, and confocal and scanning electron microscopy. The requirement for functional Gasdermin D and Caspase-1 for IL-1β production and cell death by AF-2 confirmed pyroptosis as the mode of action of AF-2. The inhibition of NLRP3 and K+ efflux reduced AF-2 mediated IL-1β production and cell death, and allowed us to conclude that AF-2 leads to Capase-1 dependent NLRP3 inflammasome-mediated cell death. The unique mode of action of plate-coated AF-2 was surprising and highlights how the physical presentation of Mincle ligands can lead to dramatically different immunological outcomes.

Subjects

Subjects :
Immunology
Immunology and Allergy

Details

ISSN :
15732576 and 03603997
Database :
OpenAIRE
Journal :
Inflammation
Accession number :
edsair.doi...........ac3db86c06f1d4148f70500cb9a3db1b