Siglec-14-Mediated Inflammatory Responses to Carbon Nanomaterials

Carbon nanomaterials (CNM), including carbon nanotubes (CNT) and graphene nanoplatelets (GNP), are expected to have diverse industrial applications due to their unique physical properties. However, concerns have been raised regarding their toxicity in humans. In this context, risk assessment must include an understanding of the molecular mechanisms underlying human recognition of CNM. We have recently identified human sialic acid-binding immunoglobulin-like lectin (Siglec)-14 as a CNT-recognizing receptor. Since no rodent orthologs for Siglec-14 exist, previous rodent toxicological studies may underestimate CNM toxicity in humans. Therefore, in this study, we investigate Siglec-14 responses to various CNM. Siglec-14 recognizes various types of CNM via its extracellular aromatic cluster with a similar affinity, regardless of size and shape. Ultrathin single-walled CNT (SWCNT) and spherical carbon black nanoparticles (CBNP) activated macrophage Siglec-14 signaling, leading to IL-8 production. Notably, GNP as well as long needle-like MWCNT not only activate this inflammatory signal but also cause phagosomal damage, leading to the release of IL-1β, the most prominent pro-inflammatory cytokine. In mice transduced with Siglec-14, intratracheal injection of GNP or long needle-like MWCNT caused lung inflammation, whereas injection of SWCNT or CBNP did not. Taken together, these results suggest that CNM-induced inflammation requires two processes: macrophage receptor ligation and phagosomal damage. This indicates that CNM may be safe unless they cause damage to the macrophage phagosome.