Dendritic cell (DC) immunoreceptor (DCIR) is a receptor that contains a carbohydrate recognition domain. Thus, several carbohydrates like mannose, glucose, fucose, and many others bind to DCIR. In addition, it appears that molecules like asialo-N-glycans also bind to DCIR, but the role of this binding remains unclear. DCIR is especially expressed in abundance in immune cells and bone cells.
Early studies show that DCIR deficient mice develop enthesitis and sialadenitis, making them prone to autoimmune conditions. In addition, DCIR deficient mice are also susceptible to collagen-induced arthritis (CIA), an animal model for rheumatoid arthritis, and experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis, suggesting that this molecule is involved in the regulation of these autoimmune diseases. Further, DCIR deficient mice develop ankylotic changes in the ankle joint. This suggests the important role of DCIR in both bone metabolism and the immune system.
In a new study by Professor Yoichiro Iwakura and colleagues from the Center for Animal Disease Models, Research Institution for Biological Sciences, Tokyo University of Science investigated the role of asialo-biantennary N-glycan(s) (NA2) binding to DCIR. The researchers found that macrophages, osteoclasts, and osteoblasts have high DCIR ligands expression. Additionally, they discovered that DCIR interacts with N-glycans. As DCIR is highly expressed in myeloid-lineage cells like macrophages and DCs, they also examined the expression of DCIR in osteoclasts, and indeed they found DCIR expression in these cells. Next, researchers examined the role of NA2 on osteoclastogenesis in human cells. They found that osteoclastogenesis was significantly suppressed when treated with NA2.
Additionally, in the in-vitro study, they found that DCIR binding to NA2 was higher in cells that lacked the terminal sialic acid in complex N-glycan. Next, researchers explored the effect of neuraminidase treatment, which results in desialylated glycans. They found that such treatment increased NA2 and DCIR binding and thus suppressed the osteoclast formation. They also found that neuraminidase did not work in DCIR deficient osteoclasts, indicating that DCIR mediates osteoclast suppression.
This study suggests that a large proportion of NA2 is masked by sialic acid under normal physiological conditions, and they become more available when treated with neuraminidase. This results in a more significant binding of NA2 to human DCIR and thus various physiological effects.
Thus, this study could show that endogenous NA2 can bind to DCIR. Further, the study analyzed the effects of NA2 on osteoclastogenesis and identified NA2 as a functional ligand for human DCIR. It also showed that exposure to NA2 can be increased in humans by removing the terminal sialic acid of N-glycans. One of the ways of doing it is with the help of the neuraminidase enzyme. This results in increased NA2 and DCIR binding and suppresses osteoclastogenesis. These findings also suggest that NA2 and DCIR axis plays an important role in maintaining homeostasis of the bone and immune system.
Since the development of CIA was much aggravated in DCIR deficient mice, researchers analyzed the effect of administering neuraminidase on the genetically modified mice susceptible to CIA. They found that when CIA was induced after administering neuraminidase, the arthritis scores were much lower in the mice. Similarly, researchers studied the role of neuraminidase in preventing the development of EAE in mice. They found that the injection of neuraminidase ameliorated the development of EAE. However, this treatment had no impact on DCIR deficient mice.
The new study by Tokyo University of Science scientists is one of the first studies of its kind that explored the role of NA2 ligands, their role in modulating the NA2-DCIR axis, and thus having an impact on the immune and bone system. Future studies will look into how and where the terminal sialic acid content of N-glycans is regulated in the cells. But it could show that removing terminal sialic acid is one of the ways of modulating the activity of bone and the immune system. Additionally, there is a further need to understand the greater role of the DCIR-NA2 axis in human health. The authors findings will pave the way to develop new therapeutic approaches to the treatment of immune and bone metabolic diseases.
Kaifu, T., Yabe, R., Maruhashi, T., Chung, S.-H., Tateno, H., Fujikado, N., Hirabayashi, J., & Iwakura, Y. (2021). DCIR and its ligand asialo-biantennary N-glycan regulate DC function and osteoclastogenesis. Journal of Experimental Medicine, 218(12), e20210435. https://doi.org/10.1084/jem.20210435