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Aryl-functionalised α,α′-Trehalose 6,6′-Glycolipid Induces Mincle-independent Pyroptotic Cell Death
- Source :
- Inflammation.
- Publication Year :
- 2023
- Publisher :
- Springer Science and Business Media LLC, 2023.
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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 :
- Immunology
Immunology and Allergy
Subjects
Details
- ISSN :
- 15732576 and 03603997
- Database :
- OpenAIRE
- Journal :
- Inflammation
- Accession number :
- edsair.doi...........ac3db86c06f1d4148f70500cb9a3db1b