“Siglec-14” Receptor in Human Macrophages Detects Carbon Nanotubes and Provokes Inflammation, Study Finds

Carbon nanotubes (CNTs) are innovative nanomaterials with potential applications in several fields. However, we do not fully know the risks they pose to humans, and studies have shown that multi-walled CNTs trigger an immune response in mice. Now, scientists in Japan have identified that “Siglec-14” receptors on macrophages are involved in human CNT recognition. Their findings provide some much-needed insight into the cellular mechanisms underlying the interactions between biological systems and CNTs.

In a new study, researchers from Japan found that aromatic groups on the extracellular Siglec-14 receptor found on macrophages recognize carbon nanotubes and then mediate immune reactions against them. Image Credit: Masafumi Nakayama of Ritsumeikan University, Japan

​​​​​​Carbon nanotubes (CNTs) have become a mainstay of the nanotechnology field. Finding innovative applications throughout materials science, electronics, and medicine, CNTs have attracted a great deal of attention from researchers in recent years. However, the International Secretariat of Chemistry (ChemSec) has moved to mark CNT on “Substitute It Now!” database of chemicals that may be restricted for use. In fact, because of their persistence in nature and potential toxicity to humans, ChemSec has suggested that an adequate risk assessment of CNTs to human health is urgently needed.

Once they enter the body, and like asbestos, CNTs are targeted by the immune system and preferably ingested by macrophages. The subsequent inflammatory response – involving inflammasome and interleukin-1β (IL-1β) secretion – can develop into chronic inflammation, fibrosis, and even mesothelioma, as seen in rodent models. Unfortunately, how human macrophages recognize CNTs is still a mystery.

Now, a research team in Japan has discovered that extracellular receptors, namely, immunoglobulin-binding lectins such as sialic acid (Siglec) -5 and -14, are involved in CNT recognition by human macrophages. The team, which included Professor Masafumi Nakayama of Ritsumeikan University, built on their previous work confirming how mouse T-cell mucin immunoglobulin 4 (Tim4) receptors bind to the CNT via the aromatic-aromatic interface. The findings from this study have published in Natural Nanotechnology. “We hypothesize that aromatic groups are essential for CNT recognition. But at that time, it was not proven that the Tim4 receptor plays a role in CNT engulfment by human macrophages.” said Prof. Nakayama on his motivation to study.

This group uses a three-dimensional protein-based structure in silicon screening and ectopic life Siglec-14 receptor expression to validate how aromatic rings facilitate Siglec-CNT interactions. Through molecular dynamics simulations, the team discovered interactions of aromatic residues in the extracellular loop of Siglec-5 and the CNT. On the other hand, they found that Siglec-14 initiates CNT phagocytosis dependent on the splenic tyrosine kinase (Syk) pathway and IL-1β release by macrophages. CNT detection was enhanced in human Siglec-14-expressing mouse macrophages, and importantly, the team noticed that this interaction greatly exacerbated pulmonary inflammation.

Finally, the drug fostatinib, which is a Syk inhibitor, appears to block Siglec-14-mediated proinflammatory signaling cascades. “This is an encouraging result because this drug can overcome inflammation caused by CNT,” said Prof. Nakayama when explaining the importance of teamwork.

While the team is excited about their breakthrough, they are careful to note that these findings do not mean CNTs have asbestos-like toxicity. Estimating CNT toxicity will depend on a number of other variables: route of exposure, dose of CNT received, and the size and shape of the CNT involved. At this stage, more detailed studies are needed to accurately measure the risks posed to humans.

However, Prof. Nakayama is proud to know that his team has laid the groundwork to help develop safer CNTs. he concluded, “Even if CNTs are likely to cause inflammatory disease, our findings will help develop new therapies, such as the anti-Siglec-14 monoclonal antibody and fostamatinib, to prevent such conditions.”


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