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Mincle is an ITAM-coupled activating receptor that senses damaged cells

Nature Immunology volume 9, pages 1179–1188 (2008)Cite this article

Abstract

Macrophage-inducible C-type lectin (Mincle) is expressed mainly in macrophages and is induced after exposure to various stimuli and stresses. Here we show that Mincle selectively associated with the Fc receptor common γ-chain and activated macrophages to produce inflammatory cytokines and chemokines. Mincle-expressing cells were activated in the presence of dead cells, and we identified SAP130, a component of small nuclear ribonucloprotein, as a Mincle ligand that is released from dead cells. To investigate whether Mincle is required for normal responses to cell death in vivo, we induced thymocyte death by irradiating mice and found that transient infiltration of neutrophils into the thymus could be blocked by injection of Mincle-specific antibody. Our results suggest that Mincle is a receptor that senses nonhomeostatic cell death and thereby induces the production of inflammatory cytokines to drive the infiltration of neutrophils into damaged tissue.

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Figure 1: Mincle is associated with FcRγ through charged residues.
Figure 2: Mincle transduces activation signals into macrophages in an FcRγ-dependent way.
Figure 3: FcRγ transduces Mincle signaling through ITAM.
Figure 4: Dead cells mediate activation signals through Mincle.
Figure 5: SAP130 selectively binds to Mincle.
Figure 6: SAP130 acts as a functional ligand of Mincle.
Figure 7: Mincle induction and neutrophil infiltration after whole-body irradiation.
Figure 8: Anti-Mincle blocks neutrophil infiltration after thymocyte death.

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Acknowledgements

We thank S. Akira (Osaka University) for MyD88-deficient mice on a B6 background; J.S. Verbeek (Leiden University) for FcγRI-deficient and FcγRIII-deficient mice; S. Nagata (Kyoto University) for 'leucine-zippered' FasL; S. Seki, T. Aoyama, A. Iwamatsu, Y. Tatsumi and T. Ishikawa for technical assistance; T. Kaisho, M. Tanaka, Y. Miyake, H. Ohno, H. Yoshida, S. Ishido, T. Sugiyama, T. Imanishi, O. Takeuchi and T. Iwahara for discussions; and H. Yamaguchi for secretarial assistance.

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Authors and Affiliations

  1. Laboratory for Cell Signaling, RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, 230-0045, Kanagawa, Japan

    Sho Yamasaki, Eri Ishikawa, Machie Sakuma & Takashi Saito

  2. Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, 849-8501, Japan

    Hiromitsu Hara

  3. Centre for Computational Biology, The Hospital for Sick Children, Toronto, M5G 1X8, Ontario, Canada

    Koji Ogata

  4. World Premier International Immunology Frontier Research Center, Osaka University, Suita, 565-0871, Japan

    Takashi Saito

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Contributions

S.Y. designed experiments; E.I., M.S. and S.Y. did experiments; S.Y. wrote the paper; H.H. provided knockout mice; K.O. did molecular modeling; and T.S. supervised the research.

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Correspondence to Sho Yamasaki or Takashi Saito.

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Yamasaki, S., Ishikawa, E., Sakuma, M. et al. Mincle is an ITAM-coupled activating receptor that senses damaged cells. Nat Immunol 9, 1179–1188 (2008). https://doi.org/10.1038/ni.1651

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