Rheumatoid arthritis is a chronic, autoimmune disease that primarily affects the joints, causing pain, stiffness, and swelling. It occurs when the immune system mistakenly attacks the body’s own tissues, causing inflammation and damage to joints and other organs.
A research team at Osaka University has discovered a protein complex that plays an important role in the development of rheumatoid arthritis. Furthermore, their findings show that celastrol, an active compound found in medicinal herbs, effectively blocks disease progression by inhibiting this protein complex.
It is widely understood that having a strong immune system is beneficial. However, there are times when the immune system malfunctions and starts attacking your body. This phenomenon, known as autoimmunity, is responsible for various diseases such as rheumatoid arthritis, Crohn’s disease, type 1 diabetes, and celiac disease. To address these symptoms, it is essential to elucidate the underlying mechanisms that cause their development.
In a recently published study, scientific immunology, a research team from Osaka University worked to fill this gap in our understanding. They identified a protein complex involved in promoting rheumatoid arthritis. This complex is made up of two proteins, specifically he COMMD3 and COMMD8. In addition, they found that celastrol, a compound extracted from the roots of a medicinal plant commonly referred to as “the vine of the thunder god,” was an effective inhibitor of the COMMD3/8 complex.
In silico modeling of the celastrol-binding COMMD3/8 complex. Credit: 2023 Shirai et al., Science Immunology
“Although the COMMD3/8 complex was previously shown to enhance humoral immune responses, its role in autoimmune diseases remained unclear,” says lead author Kazuhiro Suzuki. The research team generated a mouse model in which COMMD3 expression can be turned off. “Deletion of COMMD3 degrades COMMD8, resulting in the disappearance of the COMMD3/8 complex,” explains Taiichiro Shirai, the lead author of the study.
Absence of the COMMD3/8 complex impairs the humoral immune response.
“The decrease in the number of antibody-producing cells suggests that the COMMD3/8 complex plays an important role in the autoimmune response,” says Taiichiro Shirai.
The researchers then used a mouse model of rheumatoid arthritis. They suppressed COMMD3 expression as soon as the mice showed the first symptoms. Doing so halted disease progression, and the COMMD3/8 complex was shown to drive autoimmune responses.
Effect of COMMD3/8 complex deficiency (A) and celastrol treatment (B) on disease progression in a mouse model of rheumatoid arthritis. Credit: 2023 Shirai et al., Science Immunology
“After establishing the importance of the complex in autoimmunity, we set out to identify compounds that could interfere with complex formation,” explains Kazuhiro Suzuki. “Our chemical screen identified celastrol as the most potent inhibitor of the COMMD3/8 complex.”
Celastrol is Tripteridium wilfoldi, is a medicinal herb known to have anti-inflammatory properties, but its mechanism of action is not fully elucidated. This study showed that celastrol covalently binds to COMMD3 and prevents the formation of the COMMD3/8 complex, thereby impairing antibody responses and blocking the progression of rheumatoid arthritis in a mouse model.
Because the COMMD3/8 complex is central to the pathogenesis of rheumatoid arthritis and the progression of autoimmunity in general, celastrol is a promising therapeutic target for autoimmune diseases, and celastrol may be used in the development of therapeutics for rheumatoid arthritis and other autoimmune diseases. A future disease that will be a particularly exciting lead.
Reference: “Celastrol suppresses humoral immune response and autoimmunity by targeting the COMMD3/8 complex” Taiichiro Shirai, Akiko Nakai, Emiko Ando, Jun Fujimoto, Sarah Leach, Takao Arimori, Higo Daisuke, Floris J. Van Eerden, Janyarchy Truw, Yu-Chen Liu, Daisuke Okuzaki, Masanori Murayama, Haruhiko Miyata, Kazuto Nunomura, Bangzhong Lin, Akiyoshi Tani, Atsushi Kumanogyo, Masahito Igawa, James B. Wing, Daron M. Standley, Junichi Takagi, Kazuhiro Suzuki, March 31, 2023, scientific immunology.
DOI: 10.1126/sciimmunol.adc9324
This research was funded by the Japan Society for the Promotion of Science, Japan Agency for Medical Research and Development, Japan Science and Technology Agency, Takeda Science Foundation, KANAE Foundation, and Chugai Pharmaceutical Co., Ltd.
