In silico modeling of the celastrol-bound COMMD3/8 complex. Credit: 2023 Shirai et al., Science Immunology
” We had previously revealed that the COMMD3/8 complex potentiates the humoral immune reaction, yet its function in autoimmune diseases stayed uncertain,” states Kazuhiro Suzuki, senior author. The group produced a mouse model in which the expression of COMMD3 can be turned off. “Deleting COMMD3 lead to the degradation of COMMD8 and, consequently, the disappearance of the COMMD3/8 complex,” explains Taiichiro Shirai, lead author of the study.
The lack of the COMMD3/8 complex caused an impaired humoral immune action.
” The number of cells producing antibodies reduced, recommending that the COMMD3/8 complex has an essential role in the autoimmune response,” states Taiichiro Shirai.
Then, the researchers utilized a mouse model of rheumatoid arthritis. They repressed COMMD3 expression as quickly as the mice displayed the very first symptoms. By doing so, the development of the disease stopped, suggesting that the COMMD3/8 complex promotes the autoimmune action.
Effects of COMMD3/8 complex deficiency (A) and celastrol treatment (B) on the disease development in a mouse model of rheumatoid arthritis. Credit: 2023 Shirai et al., Science Immunology
” Once we had developed the importance of the complex in autoimmunity, we went about identifying a compound that could interfere with the formation of the complex,” discusses Kazuhiro Suzuki. “Our chemical screen identified celastrol as the most powerful inhibitor of the COMMD3/8 complex.”
Celastrol is an active substance from Tripterygium wilfordii, a medicinal herb that is known to have anti-inflammatory homes, though its mechanism of action is not fully elucidated. The study revealed that celastrol binds to COMMD3 covalently and prevents the formation of the COMMD3/8 complex, therefore impairing the antibody response and obstructing 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 development of autoimmunity in basic, it is a promising therapeutic target for autoimmune conditions, and celastrol is a particularly exciting lead for establishing treatments against rheumatoid arthritis and other autoimmune diseases in the future.
Recommendation: “Celastrol suppresses humoral immune actions 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.DOI: 10.1126/ sciimmunol.adc9324.
The study was moneyed 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
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Rheumatoid arthritis is a chronic autoimmune illness that mostly affects the joints, causing discomfort, stiffness, and swelling. It happens when the immune system mistakenly assaults the bodys own tissues, leading to swelling and damage in the joints and other organs.
A team of researchers at OU has found a protein complex that plays an essential function in the development of rheumatoid arthritis. Their findings demonstrate that celastrol, the active substance found in a medical herb, effectively impedes the advancement of the disease by preventing this protein complex.
Its generally understood that having a robust immune system is useful. There are instances where the immune system breakdowns and begins to attack ones own body. This phenomenon, referred to as autoimmunity, is accountable for a series of conditions, including rheumatoid arthritis, Crohns illness, type 1 diabetes, and celiac disease. To combat these conditions, its imperative to discover the hidden mechanisms that trigger their advancement.
In a study recently released in Science Immunology, a group 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 2 proteins, particularly COMMD3 and COMMD8. In addition, they discovered that celastrol, a compound extracted from the root of a medical plant typically described as the “Thunder God vine”, is an efficient inhibitor of the COMMD3/8 complex.
” We had actually previously shown that the COMMD3/8 complex potentiates the humoral immune response, yet its role in autoimmune illness remained uncertain,” states Kazuhiro Suzuki, senior author. “Deleting COMMD3 outcomes in the destruction of COMMD8 and, consequently, the disappearance of the COMMD3/8 complex,” explains Taiichiro Shirai, lead author of the study.
By doing so, the development of the illness stopped, indicating that the COMMD3/8 complex promotes the autoimmune reaction.
They have actually determined a protein complex that plays a role in speeding up rheumatoid arthritis. They found that celastrol, a substance extracted from the root of a medicinal plant typically referred to as the “Thunder God vine”, is a reliable inhibitor of the COMMD3/8 complex.