Accumulating evidence indicates that cell death triggers sterile inflammation and that impaired clearance of dead cells causes nonresolving inflammation; however, the underlying mechanisms are still unclear. Here, we show that macrophage-inducible C-type lectin (Mincle) senses renal tubular cell death to induce sustained inflammation after acute kidney injury in mice. Mincle-deficient mice were protected against tissue damage and subsequent atrophy of the kidney after ischemia–reperfusion injury. Using lipophilic extract from the injured kidney, we identified β-glucosylceramide as an endogenous Mincle ligand. Notably, free cholesterol markedly enhanced the agonistic effect of β-glucosylceramide on Mincle. Moreover, β-glucosylceramide and free cholesterol accumulated in dead renal tubules in proximity to Mincle-expressing macrophages, where Mincle was supposed to inhibit clearance of dead cells and increase proinflammatory cytokine production. This study demonstrates that β-glucosylceramide in combination with free cholesterol acts on Mincle as an endogenous ligand to induce cell death–triggered, sustained inflammation after acute kidney injury.
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2 November 2020
Article|
August 14 2020
C-type lectin Mincle mediates cell death–triggered inflammation in acute kidney injury
Miyako Tanaka,
Conceptualization, Formal analysis, Funding acquisition, Investigation, Validation, Writing - original draft, Writing - review & editing
1
Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
2
Department of Immunometabolism, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Marie Saka-Tanaka,
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Validation, Visualization, Writing - original draft
1
Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
3
Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Kozue Ochi,
Kozue Ochi
Investigation
1
Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
2
Department of Immunometabolism, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Kumiko Fujieda,
Kumiko Fujieda
Investigation
1
Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
2
Department of Immunometabolism, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Yuki Sugiura,
Yuki Sugiura
Formal analysis, Funding acquisition, Investigation, Methodology
4
Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan
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Tomofumi Miyamoto,
Tomofumi Miyamoto
Formal analysis
5
Department of Natural Products Chemistry, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
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Hiro Kohda,
Hiro Kohda
Investigation
1
Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
2
Department of Immunometabolism, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Ayaka Ito,
Ayaka Ito
Investigation, Resources
1
Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
2
Department of Immunometabolism, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Taiki Miyazawa,
Taiki Miyazawa
Investigation
6
Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan
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Akira Matsumoto,
Akira Matsumoto
Investigation, Methodology, Writing - review & editing
6
Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan
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Seiichiro Aoe,
Seiichiro Aoe
Formal analysis, Investigation
7
Department of Home Economics, Otsuma Women's University, Tokyo, Japan
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Yoshihiro Miyamoto,
Yoshihiro Miyamoto
Investigation
8
Division of Genomic Diagnosis and Healthcare, National Cerebral and Cardiovascular Center, Suita, Japan
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Naotake Tsuboi,
Naotake Tsuboi
Conceptualization, Project administration, Supervision
3
Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan
9
Department of Nephrology, Fujita Health University School of Medicine, Toyoake, Japan
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Shoichi Maruyama,
Shoichi Maruyama
Conceptualization, Project administration, Supervision, Validation, Writing - review & editing
3
Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Makoto Suematsu,
Makoto Suematsu
Conceptualization, Funding acquisition, Supervision, Writing - review & editing
4
Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan
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Sho Yamasaki,
Sho Yamasaki
Methodology
10
Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
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Yoshihiro Ogawa,
1
Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
11
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
12
Department of Molecular and Cellular Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
13
Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology, Tokyo, Japan
Yoshihiro Ogawa: yogawa@intmed3.med.kyushu-u.ac.jp
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Takayoshi Suganami
Conceptualization, Funding acquisition, Project administration, Supervision, Validation, Writing - original draft, Writing - review & editing
1
Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
2
Department of Immunometabolism, Nagoya University Graduate School of Medicine, Nagoya, Japan
Correspondence to Takayoshi Suganami: suganami@riem.nagoya-u.ac.jp
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Miyako Tanaka
Conceptualization, Formal analysis, Funding acquisition, Investigation, Validation, Writing - original draft, Writing - review & editing
1
Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
2
Department of Immunometabolism, Nagoya University Graduate School of Medicine, Nagoya, Japan
Marie Saka-Tanaka
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Validation, Visualization, Writing - original draft
1
Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
3
Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan
Kozue Ochi
Investigation
1
Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
2
Department of Immunometabolism, Nagoya University Graduate School of Medicine, Nagoya, Japan
Kumiko Fujieda
Investigation
1
Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
2
Department of Immunometabolism, Nagoya University Graduate School of Medicine, Nagoya, Japan
Yuki Sugiura
Formal analysis, Funding acquisition, Investigation, Methodology
4
Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan
Tomofumi Miyamoto
Formal analysis
5
Department of Natural Products Chemistry, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
Hiro Kohda
Investigation
1
Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
2
Department of Immunometabolism, Nagoya University Graduate School of Medicine, Nagoya, Japan
Ayaka Ito
Investigation, Resources
1
Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
2
Department of Immunometabolism, Nagoya University Graduate School of Medicine, Nagoya, Japan
Taiki Miyazawa
Investigation
6
Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan
Akira Matsumoto
Investigation, Methodology, Writing - review & editing
6
Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan
Seiichiro Aoe
Formal analysis, Investigation
7
Department of Home Economics, Otsuma Women's University, Tokyo, Japan
Yoshihiro Miyamoto
Investigation
8
Division of Genomic Diagnosis and Healthcare, National Cerebral and Cardiovascular Center, Suita, Japan
Naotake Tsuboi
Conceptualization, Project administration, Supervision
3
Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan
9
Department of Nephrology, Fujita Health University School of Medicine, Toyoake, Japan
Shoichi Maruyama
Conceptualization, Project administration, Supervision, Validation, Writing - review & editing
3
Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan
Makoto Suematsu
Conceptualization, Funding acquisition, Supervision, Writing - review & editing
4
Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan
Sho Yamasaki
Methodology
10
Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
Yoshihiro Ogawa
Supervision, Writing - original draft, Writing - review & editing
1
Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
11
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
12
Department of Molecular and Cellular Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
13
Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology, Tokyo, Japan
Takayoshi Suganami
Conceptualization, Funding acquisition, Project administration, Supervision, Validation, Writing - original draft, Writing - review & editing
1
Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
2
Department of Immunometabolism, Nagoya University Graduate School of Medicine, Nagoya, Japan
*
M. Tanaka and M. Saka-Tanaka contributed equally to this paper.
Yoshihiro Ogawa: yogawa@intmed3.med.kyushu-u.ac.jp
Correspondence to Takayoshi Suganami: suganami@riem.nagoya-u.ac.jp
Received:
November 26 2019
Revision Received:
June 08 2020
Accepted:
July 07 2020
Online Issn: 1540-9538
Print Issn: 0022-1007
Funding:
Aichi Kidney Foundation
(NO AWARD)
Daiichi Sankyo Foundation of Life Science
(NO AWARD)
Exploratory Research for Advanced Technology
(NO AWARD)
Hori Sciences and Arts Foundation
(NO AWARD)
Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care
(NO AWARD)
Japan Agency for Medical Research and Development
(JP19gm1210009s0101)
Ministry of Education, Culture, Sports, Science and Technology
(17H05500)
NOVARTIS Foundation (Japan) for the Promotion of Science
(NO AWARD)
Ono Medical Research Foundation
(NO AWARD)
Takeda Science Foundation
(NO AWARD)
This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply.
2020
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Exp Med (2020) 217 (11): e20192230.
Article history
Received:
November 26 2019
Revision Received:
June 08 2020
Accepted:
July 07 2020
Citation
Miyako Tanaka, Marie Saka-Tanaka, Kozue Ochi, Kumiko Fujieda, Yuki Sugiura, Tomofumi Miyamoto, Hiro Kohda, Ayaka Ito, Taiki Miyazawa, Akira Matsumoto, Seiichiro Aoe, Yoshihiro Miyamoto, Naotake Tsuboi, Shoichi Maruyama, Makoto Suematsu, Sho Yamasaki, Yoshihiro Ogawa, Takayoshi Suganami; C-type lectin Mincle mediates cell death–triggered inflammation in acute kidney injury. J Exp Med 2 November 2020; 217 (11): e20192230. doi: https://doi.org/10.1084/jem.20192230
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