Intracellular metabolite β-glucosylceramide is an endogenous Mincle ligand possessing immunostimulatory activity

Masahiro Nagata, Yoshihiro Izumi, Eri Ishikawa, Ryoko Kiyotake, Rieko Doi, Satoru Iwai, Zakaria Omahdi, Toshiyuki Yamaji, Tomofumi Miyamoto, Takeshi Bamba, Shou Yamasaki

Research output: Contribution to journalArticle

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Abstract

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 intracellularmetabolite. Synthetic β-GlcCer activated myeloid cells and induced production of inflammatory cytokines; this production was abrogated inMincle-deficient cells. Sterile inflammation induced by excessive cell death in the thymus was exacerbated by hematopoieticspecific 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 × Mincle double-deficient mice. These results suggest that β-GlcCer is an endogenous ligand for Mincle and possesses immunostimulatory activity.

Original languageEnglish
Pages (from-to)E3285-E3294
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number16
DOIs
Publication statusPublished - Apr 18 2017

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Glucosylceramides
C-Type Lectins
Macrophages
Ligands
Dendritic Cells
Glycolipids
Mass Spectrometry
Glucosylceramidase
Inflammation
Myeloid Cells
Thymus Gland
Immune System
Cell Death
Magnetic Resonance Spectroscopy
Cytokines
T-Lymphocytes
Antigens
Enzymes

All Science Journal Classification (ASJC) codes

  • General

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Intracellular metabolite β-glucosylceramide is an endogenous Mincle ligand possessing immunostimulatory activity. / Nagata, Masahiro; Izumi, Yoshihiro; Ishikawa, Eri; Kiyotake, Ryoko; Doi, Rieko; Iwai, Satoru; Omahdi, Zakaria; Yamaji, Toshiyuki; Miyamoto, Tomofumi; Bamba, Takeshi; Yamasaki, Shou.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 16, 18.04.2017, p. E3285-E3294.

Research output: Contribution to journalArticle

Nagata, Masahiro ; Izumi, Yoshihiro ; Ishikawa, Eri ; Kiyotake, Ryoko ; Doi, Rieko ; Iwai, Satoru ; Omahdi, Zakaria ; Yamaji, Toshiyuki ; Miyamoto, Tomofumi ; Bamba, Takeshi ; Yamasaki, Shou. / Intracellular metabolite β-glucosylceramide is an endogenous Mincle ligand possessing immunostimulatory activity. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 16. pp. E3285-E3294.
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