Tim4 recognizes carbon nanotubes and mediates phagocytosis leading to granuloma formation
Tim4 recognizes carbon nanotubes and mediates phagocytosis leading to granuloma formation
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Tim4 识别碳纳米管并介导吞噬作用，导致肉芽肿形成
DOI：
10.1016/j.celrep.2021.108734
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发表时间：
2021
期刊：
影响因子：
8.8
通讯作者：
Nakayama M
中科院分区：
文献类型：
--
作者：
Omori S;Tsugita M;Hoshikawa Y;Morita M;Ito F;Yamaguchi SI;Xie Q;Noyori O;Yamaguchi T;Takada A;Saitoh T;Toyokuni S;Akiba H;Nagata S;Kinoshita K;Nakayama M
巨噬细胞对晶体的识别和吞噬对相关的纤维化和癌症至关重要。值得注意的是，多壁碳纳米管（MWCNTs）是纳米技术的高度代表性产物，可诱导巨噬细胞NLRP3炎性体活化并引起石棉样发病机制。然而，巨噬细胞如何有效识别其细胞表面的MWCNTs仍是未知的。在这里，我们通过靶向筛选吞噬细胞受体磷脂酰丝氨酸受体T细胞免疫球蛋白粘蛋白4 （Tim4）和Tim1作为碳晶体的模式识别受体。对接模拟研究揭示了Tim4细胞外IgV结构域芳香族残基与一维碳晶体之间的时空稳定界面。此外，crispr - cas9介导的Tim4和Tim1缺失表明，在MWCNTs直接暴露于间皮的小鼠模型中，Tim4（而非Tim1）对腹膜巨噬细胞对MWCNTs的识别和肉芽肿的形成起关键作用。这些结果表明Tim4通过芳香相互作用识别MWCNTs并介导吞噬导致肉芽肿。
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.