Tim4 recognizes carbon nanotubes and mediates phagocytosis leading to granuloma formation

Cell Reports

Shin-Ichiro Yamaguchi¹  Kengo Kinoshita¹  Masafumi Nakayama²  Tatsuya Saitoh³  Ayato Takada⁴  Masanobu Morita⁵  Shigekazu Nagata⁶  Fumiya Ito⁶  Shinya Toyokuni⁷  Misato Tsugita⁸  Satoshi Omori⁹  Yasuto Hoshikawa^1,10  Hisaya Akiba^1,11  Qilin Xie^1,12  Tomoya Yamaguchi^1,12  Osamu Noyori^1,12 

[1] CREST, Japan Science and Technology Agency (JST), Kawaguchi, Japan;Center for Low-temperature Plasma Sciences, Nagoya University, Nagoya, Japan;PRESTO, JST, Kawaguchi, Japan;Department of Cancer Biology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan;Department of Environmental Medicine and Molecular Toxicology, Tohoku University Graduate School of Medicine, Sendai, Japan;Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan;Division of Global Epidemiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan;Frontier Research Institute for Interdisciplinary Sciences, Tohoku University, Sendai, Japan;Graduate School of Information Sciences, Tohoku University, Sendai, Japan;Institute of Multidisciplinary Research for Advanced Materials (IMRAM), Tohoku University, Sendai, Japan;Laboratory of Bioresponse Regulation, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan;Laboratory of Immunology and Microbiology, College of Pharmaceutical Sciences, Ritsumeikan University, Kusatsu, Japan;

关键词: Tim-4;    Tim-1;    Caspase-1;    IL-1β;    nanomaterials;    molecular dynamics simulation;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown