Helicobacter pylori causes gastritis, which has been attributed to the development of H. pylori–specific T cells during infection. However, the mechanism underlying innate immune detection leading to the priming of T cells is not fully understood, as H. pylori evades TLR detection. Here, we report that H. pylori metabolites modified from host cholesterol exacerbate gastritis through the interaction with C-type lectin receptors. Cholesteryl acyl α-glucoside (αCAG) and cholesteryl phosphatidyl α-glucoside (αCPG) were identified as noncanonical ligands for Mincle (Clec4e) and DCAR (Clec4b1). During chronic infection, H. pylori–specific T cell responses and gastritis were ameliorated in Mincle-deficient mice, although bacterial burdens remained unchanged. Furthermore, a mutant H. pylori strain lacking αCAG and αCPG exhibited an impaired ability to cause gastritis. Thus H. pylori–specific modification of host cholesterol plays a pathophysiological role that exacerbates gastric inflammation by triggering C-type lectin receptors.
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4 January 2021
Article|
September 29 2020
Helicobacter pylori metabolites exacerbate gastritis through C-type lectin receptors
Masahiro Nagata,
Masahiro Nagata
Conceptualization, Investigation, Validation, Writing - original draft, Writing - review & editing
1
Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
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Kenji Toyonaga,
Kenji Toyonaga
Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
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Eri Ishikawa,
Eri Ishikawa
Conceptualization, Investigation, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
2
Laboratory of Molecular Immunology, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan
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Shojiro Haji,
Shojiro Haji
Investigation
1
Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
3
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka, Japan
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Nobuyuki Okahashi,
Nobuyuki Okahashi
Data curation, Investigation
4
Department of Bioinformatics Engineering, Graduate School of Information Science and Technology, Osaka University, Suita, Osaka, Japan
5
Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan
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Masatomo Takahashi,
Masatomo Takahashi
Investigation
6
Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Fukuoka, Japan
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Yoshihiro Izumi,
Yoshihiro Izumi
Investigation
6
Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Fukuoka, Japan
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Akihiro Imamura,
Akihiro Imamura
Resources
7
Department of Applied Bioorganic Chemistry, Gifu University, Gifu, Gifu, Japan
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Koichi Takato,
Koichi Takato
Resources
7
Department of Applied Bioorganic Chemistry, Gifu University, Gifu, Gifu, Japan
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Hideharu Ishida,
Hideharu Ishida
Resources
7
Department of Applied Bioorganic Chemistry, Gifu University, Gifu, Gifu, Japan
8
Center for Highly Advanced Integration of Nano and Life Sciences (G-CHAIN), Gifu University, Gifu, Gifu, Japan
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Shigenori Nagai,
Shigenori Nagai
Methodology
9
Department of Molecular Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
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Petr Illarionov,
Petr Illarionov
Conceptualization, Resources, Writing - review & editing
10
School of Biosciences, University of Birmingham, Birmingham, UK
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Bridget L. Stocker,
Bridget L. Stocker
Resources
11
School of Chemical and Physical Sciences, Victoria University of Wellington, Wellington, New Zealand
12
Centre for Biodiscovery, Victoria University of Wellington, Wellington, New Zealand
13
Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand
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Mattie S.M. Timmer,
Mattie S.M. Timmer
Resources
11
School of Chemical and Physical Sciences, Victoria University of Wellington, Wellington, New Zealand
12
Centre for Biodiscovery, Victoria University of Wellington, Wellington, New Zealand
13
Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand
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Dylan G.M. Smith,
Dylan G.M. Smith
Investigation
14
School of Chemistry and Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Parkville, Victoria, Australia
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Spencer J. Williams,
Spencer J. Williams
Funding acquisition, Resources, Supervision, Writing - review & editing
14
School of Chemistry and Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Parkville, Victoria, Australia
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Takeshi Bamba,
Takeshi Bamba
Funding acquisition, Supervision, Writing - review & editing
6
Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Fukuoka, Japan
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Tomofumi Miyamoto,
Tomofumi Miyamoto
Resources
15
Department of Natural Products Chemistry, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Fukuoka, Japan
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Makoto Arita,
Makoto Arita
Data curation, Funding acquisition, Investigation, Methodology, Resources, Software, Validation, Visualization, Writing - review & editing
5
Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan
16
Cellular and Molecular Epigenetics Laboratory, Graduate School of Medical Life Science, Yokohama City University, Yokohama, Kanagawa, Japan
17
Division of Physiological Chemistry and Metabolism, Graduate School of Pharmaceutical Sciences, Keio University, Minato-ku, Tokyo, Japan
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Ben J. Appelmelk,
Ben J. Appelmelk
Resources, Writing - review & editing
18
Molecular Microbiology/Medical Microbiology and Infection Control, Amsterdam University Medical Centers, Amsterdam, Netherlands
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Sho Yamasaki
1
Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
2
Laboratory of Molecular Immunology, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan
19
Division of Molecular Design, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Fukuoka, Japan
20
Division of Molecular Immunology, Medical Mycology Research Center, Chiba University, Chiba, Japan
Correspondence to Sho Yamasaki: yamasaki@biken.osaka-u.ac.jp
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Masahiro Nagata
Conceptualization, Investigation, Validation, Writing - original draft, Writing - review & editing
1
Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
Kenji Toyonaga
Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
Eri Ishikawa
Conceptualization, Investigation, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
2
Laboratory of Molecular Immunology, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan
Shojiro Haji
Investigation
1
Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
3
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka, Japan
Nobuyuki Okahashi
Data curation, Investigation
4
Department of Bioinformatics Engineering, Graduate School of Information Science and Technology, Osaka University, Suita, Osaka, Japan
5
Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan
Masatomo Takahashi
Investigation
6
Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Fukuoka, Japan
Yoshihiro Izumi
Investigation
6
Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Fukuoka, Japan
Akihiro Imamura
Resources
7
Department of Applied Bioorganic Chemistry, Gifu University, Gifu, Gifu, Japan
Koichi Takato
Resources
7
Department of Applied Bioorganic Chemistry, Gifu University, Gifu, Gifu, Japan
Hideharu Ishida
Resources
7
Department of Applied Bioorganic Chemistry, Gifu University, Gifu, Gifu, Japan
8
Center for Highly Advanced Integration of Nano and Life Sciences (G-CHAIN), Gifu University, Gifu, Gifu, Japan
Shigenori Nagai
Methodology
9
Department of Molecular Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
Petr Illarionov
Conceptualization, Resources, Writing - review & editing
10
School of Biosciences, University of Birmingham, Birmingham, UK
Bridget L. Stocker
Resources
11
School of Chemical and Physical Sciences, Victoria University of Wellington, Wellington, New Zealand
12
Centre for Biodiscovery, Victoria University of Wellington, Wellington, New Zealand
13
Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand
Mattie S.M. Timmer
Resources
11
School of Chemical and Physical Sciences, Victoria University of Wellington, Wellington, New Zealand
12
Centre for Biodiscovery, Victoria University of Wellington, Wellington, New Zealand
13
Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand
Dylan G.M. Smith
Investigation
14
School of Chemistry and Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Parkville, Victoria, Australia
Spencer J. Williams
Funding acquisition, Resources, Supervision, Writing - review & editing
14
School of Chemistry and Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Parkville, Victoria, Australia
Takeshi Bamba
Funding acquisition, Supervision, Writing - review & editing
6
Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Fukuoka, Japan
Tomofumi Miyamoto
Resources
15
Department of Natural Products Chemistry, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Fukuoka, Japan
Makoto Arita
Data curation, Funding acquisition, Investigation, Methodology, Resources, Software, Validation, Visualization, Writing - review & editing
5
Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan
16
Cellular and Molecular Epigenetics Laboratory, Graduate School of Medical Life Science, Yokohama City University, Yokohama, Kanagawa, Japan
17
Division of Physiological Chemistry and Metabolism, Graduate School of Pharmaceutical Sciences, Keio University, Minato-ku, Tokyo, Japan
Ben J. Appelmelk
Resources, Writing - review & editing
18
Molecular Microbiology/Medical Microbiology and Infection Control, Amsterdam University Medical Centers, Amsterdam, Netherlands
Sho Yamasaki
Funding acquisition, Project administration, Supervision, Writing - original draft
1
Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
2
Laboratory of Molecular Immunology, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan
19
Division of Molecular Design, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Fukuoka, Japan
20
Division of Molecular Immunology, Medical Mycology Research Center, Chiba University, Chiba, Japan
Correspondence to Sho Yamasaki: yamasaki@biken.osaka-u.ac.jp
Received:
April 27 2020
Revision Received:
July 17 2020
Accepted:
August 18 2020
Online Issn: 1540-9538
Print Issn: 0022-1007
Funding:
Australian Research Council
(DP160100597)
Japan Agency for Medical Research and Development
(JP19gm0910010)
Japan Society for the Promotion of Science
(JP17H04087)
Takeda Science Foundation
(NO AWARD)
© 2020 Nagata et al.
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 (2021) 218 (1): e20200815.
Article history
Received:
April 27 2020
Revision Received:
July 17 2020
Accepted:
August 18 2020
Citation
Masahiro Nagata, Kenji Toyonaga, Eri Ishikawa, Shojiro Haji, Nobuyuki Okahashi, Masatomo Takahashi, Yoshihiro Izumi, Akihiro Imamura, Koichi Takato, Hideharu Ishida, Shigenori Nagai, Petr Illarionov, Bridget L. Stocker, Mattie S.M. Timmer, Dylan G.M. Smith, Spencer J. Williams, Takeshi Bamba, Tomofumi Miyamoto, Makoto Arita, Ben J. Appelmelk, Sho Yamasaki; Helicobacter pylori metabolites exacerbate gastritis through C-type lectin receptors. J Exp Med 4 January 2021; 218 (1): e20200815. doi: https://doi.org/10.1084/jem.20200815
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