2. Academic Validation
  3. Intracellular metabolite β-glucosylceramide is an endogenous Mincle ligand possessing immunostimulatory activity

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

  • Proc Natl Acad Sci U S A. 2017 Apr 18;114(16):E3285-E3294. doi: 10.1073/pnas.1618133114.
Masahiro Nagata 1,  Yoshihiro Izumi 2,  Eri Ishikawa 1,  Ryoko Kiyotake 1,  Rieko Doi 1,  Satoru Iwai 1,  Zakaria Omahdi 1,  Toshiyuki Yamaji 3,  Tomofumi Miyamoto 4,  Takeshi Bamba 2,  Sho Yamasaki 5 6 7
Affiliations

Affiliations

  • 1 Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
  • 2 Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
  • 3 Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo 162-8640, Japan.
  • 4 Department of Natural Products Chemistry, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
  • 5 Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan; yamasaki@bioreg.kyushu-u.ac.jp.
  • 6 Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, 565-0871, Japan.
  • 7 Division of Molecular Immunology, Medical Mycology Research Center, Chiba University, Chiba 260-8673, Japan.
PMID: 28373578 DOI: 10.1073/pnas.1618133114
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 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 × Mincle double-deficient mice. These results suggest that β-GlcCer is an endogenous ligand for Mincle and possesses immunostimulatory activity.

Keywords

C-type lectin receptors; Gaucher disease; ceramides; glycolipids; inflammation.

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