Regulation of receptors and ligands in immune cells: A

image: neuraminidase suppresses autoimmune arthritis and encephalomyelitis by inhibiting the activity of dendritic cells and osteoclasts through the elimination of sialic acid, thus exposing the asialo-biantennial N-glycan (NA2) and generating inhibitory signals via the dendritic cell immunoreceptor (DCIR).
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Credit: Yoichiro Iwakura from Tokyo University of Science

Immune cells play a key role in mediating inflammatory responses. A disruption of the signaling mechanisms that operate in immune cells can trigger chronic inflammatory diseases like rheumatoid arthritis that cause pain and swelling in the joints. One such immune cell known to be involved in autoimmune diseases is the dendritic cell. The activity of dendritic cells is regulated by the dendritic cell immunoreceptor (DCIR) present on their surface, which includes a carbohydrate recognition domain that can bind to sugar fragments present on other proteins or cell surfaces, d ‘in a calcium dependent manner. The activity of osteoclasts, involved in bone degradation, is also regulated by DCIR. However, little is known about the interaction partners of DCIR that help mediate inflammatory responses.

A team of Japanese researchers led by Professor Yoichiro Iwakura of the Department of Experimental Animal Sciences, Research Institute for Biomedical Sciences, Tokyo University of Science, have now deepened their understanding of the mechanisms underlying the activity. DCIR. In their previous work, the researchers reported that mice deficient in DCIR spontaneously develop arthritis and bone metabolic disorders. Based on this observation, in a recent study published in the Journal of Experimental Medicine, they sought to elucidate DCIR binding partners and immune signaling mechanisms involved in inflammatory diseases. “In this study, we identified a new functional ligand for DCIR, possibly involved in the pathogenesis of arthritis and other autoimmune diseases such as multiple sclerosis. We hope that our work can advance research in immunology and glycobiology in inflammatory diseases. explains Professor Iwakura.

The researchers began by identifying potential ligands (molecules that bind to cellular receptors) of DCIR on immune and bone cells, and found that DCIR binds to glycoproteins on the surface of macrophages and osteoclasts, the latter of which bind differentiating macrophages derived from bone marrow (BMM), and involved in degeneration and bone remodeling. Upon further characterization of the glycoprotein, they noted that this interaction was specific to “asialo-biantennial N-glycan (NA2)”, a complex carbohydrate moiety comprising various sugar molecules.

After identifying the DCIR ligand, the team then set out to understand the effect of DCIR on osteoclast differentiation and “osteoclastogenesis,” a process contributing to bone loss. Interestingly, DCIR-deficient cells showed a significant increase in the expression of genes associated with osteoclastogenesis. As the researchers speculated, expression of DCIR significantly suppressed osteoclast differentiation, thus suggesting DCIR as an independent inhibitor of osteoclastogenesis. Further confirming this finding, a mutant version of DCIR, unable to recognize carbohydrate residues, was found not to exhibit this inhibitory effect.

The role of DCIR in the differentiation of osteoclasts and its interaction ligand, NA2, now decoded, the team then examined the effect of NA2 on osteoclastogenesis. Consistent with their previous finding, NA2 treatment suppressed the differentiation of osteoclasts from wild-type BMMs but not DCIR-deficient cells, highlighting the role of NA2 as a functional ligand specific to DCIR which suppresses osteoclastogenesis.

Going further, the researchers treated models of mouse autoimmune diseases with neuraminidase, an enzyme that removes terminal “sialic acid” residues from N-glycan, thereby enhancing NA2 exposure. To their delight, neuraminidase treatment further suppressed autoimmune diseases like autoimmune arthritis or experimental autoimmune encephalomyelitis, again in a DCIR dependent manner! Additionally, neuraminidase treatment improved inflammation and associated bone loss in a mouse model of arthritis, confirming their findings. in vitro and in vivo. The inhibitory effect of the DCIR-NA2 interaction on autoimmune diseases has been shown to be mediated by the suppression of the antigen presenting capacity of dendritic cells and the subsequent decrease in the activation of other immune cells. that contribute to inflammation.

All these results, taken together, highlight a novel mechanism of regulation of DCIR signaling involved in the suppression of autoimmunity and excessive bone loss. Commenting on the clinical applications of their work, Professor Iwakura observes, “Our results should contribute to the understanding of the pathogenesis of human autoimmune diseases such as rheumatoid arthritis and to the development of new therapies for the treatment of metabolic immune and bone diseases.”

This study brings us closer to resolving the complex immune mechanisms of autoimmune diseases, thus paving the way for effective and targeted treatments.




Authors: Tomonori Kaifu1, 2.5, Rikio Yabe1.5, Takumi Maruhashi1.3.5, Soo Hyun Chung1,2,5, Hiroaki Tateno4, Noriyuki Fujikado1.2, June Hirabayashi4 and Yoichiro Iwakura1,2,6


  1. Center for Animal Disease Models, Biological Sciences Research Institute, Tokyo University of Sciences
  2. Basic Research for Evolutionary Science and Technology (CREST), Japan Science and Technology Agency
  3. Japanese Society for the Promotion of Science (JSPS)
  4. Glycan Lectin Engineering Team, Research Center for Stem Cell Engineering, National Institute of Advanced Industrial Science and Technology (AIST)
  5. These authors are equal contributors to this work.
  6. corresponding author

Current address:

Tomonori Kaifu: Division of Immunology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University

Rikio Yabe: Division of Molecular Immunology, Medical Mycology Research Center, Chiba University

Takumi Maruhashi: Laboratory of Molecular Immunology, Institute of Quantitative Biosciences, University of Tokyo

Noriyuki Fujikado: Lilly Research Laboratories, Lilly Biotechnology Center, Eli Lilly and Company

Jun Hirabayashi: Tokai National Higher Education and Research System, Nagoya University

Further information

Professor Yoichiro Iwakura
Center for Animal Disease Models, Biological Sciences Research Institute
Tokyo University of Science
Email: [email protected]

Speaker Tomonori Kaifu
Division of Immunology, Faculty of Medicine
Tohoku Medical and Pharmaceutical University
Email: [email protected]

Media contact

Tsutomu Shimizu
Public relations divisions
Tokyo University of Science
E-mail: [email protected]

Yukiyo sekine
Public relations office
Tohoku Medical and Pharmaceutical University
E-mail: [email protected]

About Tokyo University of Science

Tokyo University of Science (TUS) is a well-known and respected university, and the largest private science research university in Japan, with four campuses in central Tokyo and its suburbs and in Hokkaido. Founded in 1881, the university has continuously contributed to the scientific development of Japan by instilling a love of science in researchers, technicians and educators.

With the mission of “To create science and technology for the harmonious development of nature, humans and society”, TUS has undertaken a wide range of research ranging from basic science to applied science. TUS has taken a multidisciplinary approach to research and has undertaken intensive studies in some of today’s most vital fields. TUS is a meritocracy where the best of science is recognized and encouraged. It is the only private university in Japan that has produced a Nobel Laureate and the only private university in Asia to produce Nobel Laureates in the natural sciences.


About Professor Yoichiro Iwakura from Tokyo University of Science

Professor Yoichiro Iwakura has been Director of the Center for Animal Disease Models at Tokyo University of Science since 2013 and has published over 670 papers since graduating from Kyoto University in 1970. He began researching interferon proteins at the university’s Institute for Viruses. Research before moving to Sloan-Kettering Cancer Institute in the United States to analyze the developmental mechanism of early mouse embryos. In 1985 he moved to the University of Tokyo where he generated over 100 genetically engineered mouse lines as director of the Center for Experimental Medicine to analyze the pathogenesis of infectious and autoimmune diseases. He retired from the University of Tokyo and became Professor Emeritus in 2012. He then joined Tokyo University of Science. He has been a visiting professor at many universities, including Dalian Medical University in China and Chiba University in Japan. His work includes the development and analysis of animal disease models and research into autoimmune and infectious diseases. He won the Hideyo Noguchi Memorial Award for Medical Science in 2015 and was selected as a Highly Cited Researcher (Thomson Reuters and Clarivate Analytics) for 6 years starting in 2014.

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