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Ritsumeikan University led group discovers immune receptor that recognizes carbon nanotubes: Succeed in suppressing onset of mesothelioma in mice


Carbon nanotubes (CNTs) exhibit high conductivity and strength, making them useful in various fields such as in developing semiconductors, batteries, biotechnology, and space exploration. However, various experiments since 2008 have shown that some CNTs (such as multi‐walled CNTs [MWCNTs]) cause mesothelioma, which is similar to the effects of asbestos. Due to this, the International Chemicals Secretariat declared CNTs as hazardous substances in 2019. Continuation of the research and development of CNTs has become a major international debate. The human immune receptor that recognizes CNTs was identified by a group working under Professor Masafumi Nakayama of the College of Life Sciences, Ritsumeikan University, including Shin‐Ichiro Yamaguchi, Qilin Xie and Assistant Professor Kota Kasahara (currently Central Pharmaceutical Research Institute, Japan Tabacco, Inc.)

Nakayama commented, "Although it is still unknown if CNTs are toxic to humans, administration of the immunoreceptor inhibitor to mice suppressed the onset of mesothelioma. We expect that the result will lead to the development of cures for health hazards in the future." The result was published in the science journal Nature Nanotechnology.

In 2009, the Nakayama group identified Tim4 protein as the receptor for MWCNTs and clarified that Tim4 is involved in MWCNT‐induced inflammation in mice. In experiments using human cells, they further revealed that even macrophages that do not express Tim4 recognize MWCNTs, suggesting that a receptor other than Tim4 is involved in human inflammation. The surface of Tim4 possesses an aromatic amino‐acid cluster that is essential for CNT recognition.

Kasahara and his colleagues examined crystalized human receptors with aromatic amino‐acid clusters among approximately 150,000 proteins and identified Siglec‐14. Using molecular dynamics simulation, they showed that Siglec‐14 stably binds to CNTs, and that Siglec‐14 recognizes MWCNTs through amino‐acid clusters, as observed for Tim4, which is consistent with the binding model. The Siglec‐14 receptor associates with adapter protein DAP12 on the surface of human macrophage cells and transduces inflammatory signals by activating the phosphorylation enzyme Syk (spleen tyrosine kinase).

The group also found that NF‐κB is activated via Syk vitalization, after which inflammatory cytokines such as IL8 are secreted, and that MWCNT phagocytosis is induced when Siglec‐14 recognizes MWCNTs in human macrophages. Phagocytosed MWCNT damages phagosomes and induces cell death and activation of the NLRP3 inflammasome, leading to inflammation. When Siglec‐14 was artificially transduced into mouse alveolar macrophages and MWCNTs were administrated, pneumonia was exacerbated as compared to that in mice no transduced with Siglec‐14. In addition, oral administration of fostamatinib, a Syk inhibitor, to the model mouse reduced the incidence of pneumonia.

This article has been translated by JST with permission from The Science News Ltd. ( Unauthorized reproduction of the article and photographs is prohibited.

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