Identification of endogenous glycolipids that activate immune responses via lectin receptors

2018 Fiscal Year Final Research Report

• Project Area: Homeostatic Regulation by Various Types of Cell Death
• Project/Area Number: 26110009
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Osaka University (2016-2018); Kyushu University (2014-2015)
• Principal Investigator: Yamasaki Sho 大阪大学, 微生物病研究所, 教授 (40312946)
• Co-Investigator(Kenkyū-buntansha): 宮本 智文 九州大学, 薬学研究院, 准教授 (40182050)
• Project Period (FY): 2014-07-10 – 2019-03-31
• Keywords: 糖脂質 / 自然免疫

Outline of Final Research Achievements

Sensing tissue damage is a crucial function of pattern recognition receptors (PRRs). However, endogenous ligand recognition by PRRs is not well documented. Macrophage inducible C-type lectin (Mincle) is a PRR that recognizes both pathogens and damaged cells. In this study, we isolated endogenous glycolipids derived from dying cells and identified a ubiquitous intracellular metabolite, β-glucosylceramide (GlcCer), as a Mincle ligand. β-GlcCer induced inflammatory and acquired immune responses via Mincle on myeloid cells. Accumulation of β-GlcCer leads to Gaucher disease, a disorder characterized mainly by systemic inflammation. In a Gaucher model in which mice are deficient in the β-GlcCer-degrading enzyme, further deletion of the Mincle gene attenuated inflammatory responses. These re- sults suggest that β-GlcCer is an endogenous Mincle ligand and acts as an immunostimulatory factor upon cell death.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

通常は代謝中間体として働く 糖脂質が，生体の危機を伝えるシグナルとなるという今回の発見は，細胞内に数多く存在する他の代謝産物も未知の 機能を有する可能性を示唆する知見である。また、 β-GlcCer蓄積はゴーシェ病の原因となること、パーキンソン病との強い関連が知られており、β-GlcCer認識免疫受容体の発見は、これらの疾患に対して新たな治療ターゲットを提供するものと期待される。