Carbon nanotube recognition by human Siglec-14 provokes inflammation

• Published in: Nature nanotechnology Vol. 18; no. 6; pp. 628 - 636
• Main Authors: Yamaguchi, Shin-Ichiro, Xie, Qilin, Ito, Fumiya, Terao, Kazuki, Kato, Yoshinobu, Kuroiwa, Miki, Omori, Satoshi, Taniura, Hideo, Kinoshita, Kengo, Takahashi, Takuya, Toyokuni, Shinya, Kasahara, Kota, Nakayama, Masafumi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2023; Nature Publishing Group
• Subjects: 631/61/350/2093; 631/61/350/354; Alveoli; Binding; Carbon; Carbon nanotubes; Chemistry and Materials Science; Immunoglobulins; Inflammation; Interleukins; Kinases; Lectins; Macrophages; Materials Science; Molecular dynamics; Molecular interactions; Monocytes; Nanotechnology; Nanotechnology and Microengineering; Nanotubes; Phagocytosis; Protein structure; Protein-tyrosine kinase; Receptors; Recognition; Signal transduction; Syk protein; Tyrosine
• ISSN: 1748-3387; 1748-3395
• DOI: 10.1038/s41565-023-01363-w

For the design and development of innovative carbon nanotube (CNT)-based tools and applications, an understanding of the molecular interactions between CNTs and biological systems is essential. In this study, a three-dimensional protein-structure-based in silico screen identified the paired immune receptors, sialic acid immunoglobulin-like binding lectin-5 (Siglec-5) and Siglec-14, as CNT-recognizing receptors. Molecular dynamics simulations showed the spatiotemporally stable association of aromatic residues on the extracellular loop of Siglec-5 with CNTs. Siglec-14 mediated spleen tyrosine kinase (Syk)-dependent phagocytosis of multiwalled CNTs and the subsequent secretion of interleukin-1β from human monocytes. Ectopic in vivo expression of human Siglec-14 on mouse alveolar macrophages resulted in enhanced recognition of multiwalled CNTs and exacerbated pulmonary inflammation. Furthermore, fostamatinib, a Syk inhibitor, blocked Siglec-14-mediated proinflammatory responses. These results indicate that Siglec-14 is a human activating receptor recognizing CNTs and that blockade of Siglec-14 and the Syk pathway may overcome CNT-induced inflammation. This study uncovers the role of aromatic clusters in the receptor extracellular loop of sialic-acid-binding immunoglobulin-like lectins that recognize carbon nanotubes and suggests inhibiting Syk signalling as a therapeutic intervention against inflammation.