Tim4 recognizes carbon nanotubes and mediates phagocytosis leading to granuloma formation
Satoshi Omori,
Misato Tsugita,
Yasuto Hoshikawa,
Masanobu Morita,
Fumiya Ito,
Shin-Ichiro Yamaguchi,
Qilin Xie,
Osamu Noyori,
Tomoya Yamaguchi,
Ayato Takada,
Tatsuya Saitoh,
Shinya Toyokuni,
Hisaya Akiba,
Shigekazu Nagata,
Kengo Kinoshita,
Masafumi Nakayama
Affiliations
Satoshi Omori
Graduate School of Information Sciences, Tohoku University, Sendai, Japan
Misato Tsugita
Frontier Research Institute for Interdisciplinary Sciences, Tohoku University, Sendai, Japan
Yasuto Hoshikawa
Institute of Multidisciplinary Research for Advanced Materials (IMRAM), Tohoku University, Sendai, Japan
Masanobu Morita
Department of Environmental Medicine and Molecular Toxicology, Tohoku University Graduate School of Medicine, Sendai, Japan
Fumiya Ito
Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan; CREST, Japan Science and Technology Agency (JST), Kawaguchi, Japan
Shin-Ichiro Yamaguchi
Laboratory of Immunology and Microbiology, College of Pharmaceutical Sciences, Ritsumeikan University, Kusatsu, Japan
Qilin Xie
Laboratory of Immunology and Microbiology, College of Pharmaceutical Sciences, Ritsumeikan University, Kusatsu, Japan
Osamu Noyori
Laboratory of Immunology and Microbiology, College of Pharmaceutical Sciences, Ritsumeikan University, Kusatsu, Japan
Tomoya Yamaguchi
Department of Cancer Biology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; PRESTO, JST, Kawaguchi, Japan
Ayato Takada
Division of Global Epidemiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan
Tatsuya Saitoh
Laboratory of Bioresponse Regulation, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan
Shinya Toyokuni
Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan; CREST, Japan Science and Technology Agency (JST), Kawaguchi, Japan; Center for Low-temperature Plasma Sciences, Nagoya University, Nagoya, Japan
Hisaya Akiba
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan
Shigekazu Nagata
Laboratory of Biochemistry and Immunology, Immunology Frontier Research Center, Osaka University, Suita, Japan
Kengo Kinoshita
Graduate School of Information Sciences, Tohoku University, Sendai, Japan; Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan; Corresponding author
Masafumi Nakayama
Frontier Research Institute for Interdisciplinary Sciences, Tohoku University, Sendai, Japan; Laboratory of Immunology and Microbiology, College of Pharmaceutical Sciences, Ritsumeikan University, Kusatsu, Japan; PRESTO, JST, Kawaguchi, Japan; Corresponding author
Summary: Macrophage recognition and phagocytosis of crystals is critical for the associated fibrosis and cancer. Of note, multi-walled carbon nanotubes (MWCNTs), the highly representative products of nanotechnology, induce macrophage NLRP3 inflammasome activation and cause asbestosis-like pathogenesis. However, it remains largely unknown how macrophages efficiently recognize MWCNTs on their cell surfaces. Here, we identify by a targeted screening of phagocyte receptors the phosphatidylserine receptors T cell immunoglobulin mucin 4 (Tim4) and Tim1 as the pattern-recognition receptors for carbon crystals. Docking simulation studies reveal spatiotemporally stable interfaces between aromatic residues in the extracellular IgV domain of Tim4 and one-dimensional carbon crystals. Further, CRISPR-Cas9-mediated deletion of Tim4 and Tim1 reveals that Tim4, but not Tim1, critically contributes to the recognition of MWCNTs by peritoneal macrophages and to granuloma development in a mouse model of direct mesothelium exposure to MWCNTs. These results suggest that Tim4 recognizes MWCNTs through aromatic interactions and mediates phagocytosis leading to granulomas.
