Intracellular metabolite [Beta]-glucosylceramide is an endogenous Mincle ligand possessing immunostimulatory activity

Sensing and reacting to tissue damage is a fundamental function of immune systems. Macrophage inducible C-type lectin (Mincle) is an activating C-type lectin receptor that senses damaged cells. Notably, Mincle also recognizes glycolipid ligands on pathogens. To elucidate endogenous glycolipids ligan...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2017-04, Vol.114 (16), p.E3285
Main Authors: Nagata, Masahiro, Izumi, Yoshihiro, Ishikawa, Eri, Kiyotake, Ryoko, Doi, Rieko, Iwai, Satoru, Omahdi, Zakaria, Yamaji, Toshiyuki, Miyamoto, Tomofumi, Bamba, Takeshi, Yamasaki, Sho
Format: Article
Language:English
Subjects:
Cell death
Cells
Clonal deletion
Cytokines
Dendritic cells
Enzymes
Glucosylceramidase
Glycolipids
Immunostimulation
Inflammation
Intracellular
Ligands
Lipids
Lipophilic
Lymphocytes T
Macrophages
Magnetic resonance spectroscopy
Mass spectrometry
Mass spectroscopy
Metabolites
Myeloid cells
Thymus
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Summary:Sensing and reacting to tissue damage is a fundamental function of immune systems. Macrophage inducible C-type lectin (Mincle) is an activating C-type lectin receptor that senses damaged cells. Notably, Mincle also recognizes glycolipid ligands on pathogens. To elucidate endogenous glycolipids ligands derived from damaged cells, we fractionated supernatants from damaged cells and identified a lipophilic component that activates reporter cells expressing Mincle. Mass spectrometry and NMR spectroscopy identified the component structure as β-glucosylceramide (GlcCer), which is a ubiquitous intracellular metabolite. Synthetic β-GlcCer activated myeloid cells and induced production of inflammatory cytokines; this production was abrogated in Mincle-deficient cells. Sterile inflammation induced by excessive cell death in the thymus was exacerbated by hematopoietic-specific deletion of degrading enzyme of β-GlcCer (β-glucosylceramidase, GBA1). However, this enhanced inflammation was ameliorated in a Mincle-deficient background. GBA1-deficient dendritic cells (DCs) in which β-GlcCer accumulates triggered antigen-specific T-cell responses more efficiently than WT DCs, whereas these responses were compromised in DCs from GBA1 x Mincle double-deficient mice. These results suggest that β-GlcCer is an endogenous ligand for Mincle and possesses immunostimulatory activity.
ISSN:0027-8424
1091-6490