2. Academic Validation
  3. Direct activation of microglia by β-glucosylceramide causes phagocytosis of neurons that exacerbates Gaucher disease

Direct activation of microglia by β-glucosylceramide causes phagocytosis of neurons that exacerbates Gaucher disease

  • Immunity. 2023 Feb 14;56(2):307-319.e8. doi: 10.1016/j.immuni.2023.01.008.
Takashi Shimizu 1,  Charles R Schutt 2,  Yoshihiro Izumi 3,  Noriyuki Tomiyasu 3,  Zakaria Omahdi 1,  Kuniyuki Kano 4,  Hyota Takamatsu 5,  Junken Aoki 4,  Takeshi Bamba 3,  Atsushi Kumanogoh 6,  Masaki Takao 7,  Sho Yamasaki 8
Affiliations

Affiliations

  • 1 Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan; Laboratory of Molecular Immunology, Immunology Frontier Research Center (IFReC), Osaka University, Suita, Osaka 565-0871, Japan.
  • 2 Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
  • 3 Division of Metabolomics, Research Center for Transomics Medicine, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan.
  • 4 Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
  • 5 Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan; Department of Immunopathology, Immunology Frontier Research Center (IFReC), Osaka University, Suita, Osaka 565-0871, Japan.
  • 6 Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan; Department of Immunopathology, Immunology Frontier Research Center (IFReC), Osaka University, Suita, Osaka 565-0871, Japan; Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Suita, Osaka 565-0871, Japan; Center for Infectious Diseases for Education and Research (CiDER), Osaka University, Suita, Osaka 565-0871, Japan.
  • 7 Department of Clinical Laboratory, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8551, Japan.
  • 8 Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan; Laboratory of Molecular Immunology, Immunology Frontier Research Center (IFReC), Osaka University, Suita, Osaka 565-0871, Japan. Electronic address: [email protected].
PMID: 36736320 DOI: 10.1016/j.immuni.2023.01.008
Abstract

Gaucher disease (GD) is the most common lysosomal storage disease caused by recessive mutations in the degrading enzyme of β-glucosylceramide (β-GlcCer). However, it remains unclear how β-GlcCer causes severe neuronopathic symptoms, which are not fully treated by current therapies. We herein found that β-GlcCer accumulating in GD activated microglia through macrophage-inducible C-type lectin (Mincle) to induce phagocytosis of living neurons, which exacerbated Gaucher symptoms. This process was augmented by tumor necrosis factor (TNF) secreted from activated microglia that sensitized neurons for phagocytosis. This characteristic pathology was also observed in human neuronopathic GD. Blockade of these pathways in mice with a combination of FDA-approved drugs, minocycline (microglia activation inhibitor) and etanercept (TNF blocker), effectively protected neurons and ameliorated neuronopathic symptoms. In this study, we propose that limiting unrestrained microglia activation using drug repurposing provides a quickly applicable therapeutic option for fatal neuronopathic GD.

Keywords

GBA; Gaucher disease; Mincle; microglia; phagocytosis; β-glucosylceramide.

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