Tokyo University of Science

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2021.03.17 Wednesday

Immune Receptor Protein Could Hold Key to Treatment of Autoimmune Diseases

Scientists show how a receptor protein plays a role in the immune response, yielding a potential therapeutic target for diseases like rheumatoid arthritis

TARM1 is a receptor protein whose role in the functioning of the immune system is unknown. In a new study, scientists from Japan have explored the potential role of TARM1 in the pathogenesis of rheumatoid arthritis by analyzing mouse models. They found that TARM1 activated dendritic cells, and development of collagen-induced arthritis (CIA) was notably suppressed in TARM1-deficient mice and by treatment with TARM1-inhibitory soluble TARM1 proteins. This makes the protein a potential therapeutic target.

Autoimmune diseases are typically caused when the immune system, whose purpose is to deal with foreign threats to the body, incorrectly recognizes the body's own proteins and cells as threats and activates immune cells to attack them. In the case of rheumatoid arthritis, a well-known autoimmune disease, immune cells erroneously attack the body's own joint components and proteins, causing painful inflammation and even the destruction of bone! Scientists from Japan have now taken a massive step toward understanding and, potentially, treating rheumatoid arthritis better, with their discovery in a brand-new study. Read on to understand how!

The development of autoimmune diseases is an incredibly complex process, involving several key players including genetic and environmental factors. Dendritic cells (DCs), which are responsible for kick-starting the immune response against infections, are one of the main immune cells involved in the pathogenesis of autoimmune diseases. All immune cells, including DCs, are equipped with a variety of receptors on their surfaces, which can either amplify or suppress the immune response. One such receptor is the T cell-interacting, activating receptor on myeloid cells-1 (TARM1). It is a member of the leukocyte immunoglobulin-like receptor family, and helps in the activation of other immune cells such as neutrophils and macrophages. TARM1's functions suggest that it may have an important role to play in the immune response, but the possibility of its role in the pathogenesis of rheumatoid arthritis remains largely unexplored.

The aforementioned team of scientists, led by Professor Yoichiro Iwakura from Tokyo University of Science, and Rikio Yabe and Shinobu Saijo from Chiba University, wanted to find out more about this association. In their study published in Nature Communications, they identified genes that were overexpressed in various mouse models of arthritis. Interestingly, they found that Tarm1 was one of many such genes. As Prof. Iwakura explains, "Tarm1 expression is elevated in the joints of rheumatoid arthritis mouse models, and the development of collagen-induced arthritis (CIA) is suppressed in TARM1-deficient mice."

The scientists observed that the immune system's response to type 2 collagen (IIC), a protein crucial for the development of CIA in mice, was suppressed in TARM1-deficient mice. They also found that the antigen-presenting ability of DCs in TARM1-deficient mice was impaired. With respect to the significance of these findings, Prof. Iwakura explains, "We have shown that TARM1 plays an important role for the maturation and activation of DCs through interaction with IIC". Finally, they injected TARM1-inhibitory soluble TARM1 proteins into the knee of a mouse with CIA. Notably, this suppressed the progression of CIA in the mouse, suggesting that TARM1 inhibition is effective in weakening autoimmune arthritis.

The team's findings about the TARM1 protein have wide implications with respect to the treatment of rheumatoid arthritis as well as other autoimmune and allergic diseases. Commenting on their important discoveries, Prof. Iwakura states, "Because excess DC activation is suggested in many autoimmune and allergic diseases, our observations suggest that TARM1 is a good target for the development of new drugs to treat such diseases."

The findings of this exciting new study surely indicate that there still remains much to be understood about autoimmune diseases like rheumatoid arthritis―and that the more we understand them, the better we can fight them!

Reference
Titles of original papers  : TARM1 contributes to development of arthritis by activating dendritic cells through recognition of collagens
Journal  : Nature Communications
DOI  : 10.1038/s41467-020-20307-9
About The Tokyo University of Science

Tokyo University of Science (TUS) is a well-known and respected university, and the largest science-specialized private research university in Japan, with four campuses in central Tokyo and its suburbs and in Hokkaido. Established in 1881, the university has continually contributed to Japan's development in science through inculcating the love for science in researchers, technicians, and educators.

With a mission of "Creating science and technology for the harmonious development of nature, human beings, and society", TUS has undertaken a wide range of research from basic to applied science. TUS has embraced a multidisciplinary approach to research and undertaken intensive study in some of today's most vital fields. TUS is a meritocracy where the best in science is recognized and nurtured. It is the only private university in Japan that has produced a Nobel Prize winner and the only private university in Asia to produce Nobel Prize winners within the natural sciences field.

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About Professor Yoichiro Iwakura from the Tokyo University of Science

Professor Yoichiro Iwakura has been the director of the Center for Animal Disease Models at the Tokyo University of Science since 2013, and has published numerous papers since his graduation from Kyoto University in 1970. He started researching interferon proteins at the university's Institute for Virus Research before moving to the 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 more than 100 lines of gene-modified mice as the 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 an Emeritus Professor in 2012. Then, he moved to the Tokyo University of Science. He has been a visiting professor for many universities including Dalian Medical University in China and Chiba University in Japan. His work involves the development and analysis of animal disease models and research on autoimmune diseases 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 from 2014.

PROFILE

IWAKURA Yoichiro Professor
https://www.tus.ac.jp/en/fac/p/index.php?657f

Funding information

This study was supported by the Science and Technology Research Promotion Program for Agriculture, Forestry, Fisheries and Food Industry; a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan; and a Grant-in-Aid for JSPS Fellows.

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