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, M. NAKAYAMA
Abstract
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.