A team of researchers at OU has discovered a protein complex that plays a crucial role in the development of rheumatoid arthritis. Furthermore, their findings demonstrate that celastrol, the active compound found in a medicinal herb, effectively hinders the advancement of the disease by inhibiting this protein complex.
It’s universally understood that having a robust immune system is beneficial. However, there are instances where the immune system malfunctions and begins to assault one’s own body. This phenomenon, known as autoimmunity, is responsible for a range of disorders, including rheumatoid arthritis, Crohn’s disease, type 1 diabetes, and celiac disease. To combat these conditions, it’s imperative to uncover the underlying mechanisms that trigger their development.
In a study recently published in Science Immunology, a team of researchers from Osaka University set out to fill this gap in our understanding. They have identified a protein complex that plays a role in accelerating rheumatoid arthritis. This complex consists of two proteins, specifically COMMD3 and COMMD8. Furthermore, they discovered that celastrol, a compound extracted from the root of a medicinal plant commonly referred to as the “Thunder God vine”, is an effective inhibitor of the COMMD3/8 complex.
“We had previously shown that the COMMD3/8 complex potentiates the humoral immune response, yet its role in autoimmune diseases remained unclear,” says Kazuhiro Suzuki, senior author. The team generated a mouse model in which the expression of COMMD3 can be switched off. “Deleting COMMD3 results in the degradation of COMMD8 and, consequently, the disappearance of the COMMD3/8 complex,” explains Taiichiro Shirai, lead author of the study.
The absence of the COMMD3/8 complex led to an impaired humoral immune response.
“The number of cells producing antibodies decreased, suggesting that the COMMD3/8 complex has an important role in the autoimmune response,” says Taiichiro Shirai.
Then, the researchers used a mouse model of rheumatoid arthritis. They repressed COMMD3 expression as soon as the mice exhibited the first symptoms. By doing so, the progression of the disease stopped, indicating that the COMMD3/8 complex promotes the autoimmune response.
“Once we had established the importance of the complex in autoimmunity, we set about identifying a compound that could interfere with the formation of the complex,” explains Kazuhiro Suzuki. “Our chemical screen identified celastrol as the most potent inhibitor of the COMMD3/8 complex.”
Celastrol is an active compound from Tripterygium wilfordii, a medicinal herb that is known to have anti-inflammatory properties, though its mechanism of action is not fully elucidated. The study showed that celastrol binds to COMMD3 covalently and prevents the formation of the COMMD3/8 complex, thus impairing the antibody response and blocking the progression of rheumatoid arthritis in the mouse model.
Because the COMMD3/8 complex is central to the pathogenesis of rheumatoid arthritis, and of the progression of autoimmunity in general, it is a promising therapeutic target for autoimmune conditions, and celastrol is a particularly exciting lead for developing treatments against rheumatoid arthritis and other autoimmune diseases in the future.
Reference: “Celastrol suppresses humoral immune responses and autoimmunity by targeting the COMMD3/8 complex” by Taiichiro Shirai, Akiko Nakai, Emiko Ando, Jun Fujimoto, Sarah Leach, Takao Arimori, Daisuke Higo, Floris J. van Eerden, Janyerkye Tulyeu, Yu-Chen Liu, Daisuke Okuzaki, Masanori A. Murayama, Haruhiko Miyata, Kazuto Nunomura, Bangzhong Lin, Akiyoshi Tani, Atsushi Kumanogoh, Masahito Ikawa, James B. Wing, Daron M. Standley, Junichi Takagi and Kazuhiro Suzuki, 31 March 2023, Science Immunology.
The study was funded by the Japan Society for the Promotion of Science, the Japan Agency for Medical Research and Development, the Japan Science and Technology Agency, the Takeda Science Foundation, the KANAE Foundation, and Chugai Pharmaceutical Co., Ltd.