Celastrol suppresses humoral immune responses and autoimmunity by targeting the COMMD3/8 complex

• Published in: Science immunology Vol. 8; no. 81; p. eadc9324
• Main Authors: Shirai, Taiichiro, Nakai, Akiko, Ando, Emiko, Fujimoto, Jun, Leach, Sarah, Arimori, Takao, Higo, Daisuke, van Eerden, Floris J, Tulyeu, Janyerkye, Liu, Yu-Chen, Okuzaki, Daisuke, Murayama, Masanori A, Miyata, Haruhiko, Nunomura, Kazuto, Lin, Bangzhong, Tani, Akiyoshi, Kumanogoh, Atsushi, Ikawa, Masahito, Wing, James B, Standley, Daron M, Takagi, Junichi, Suzuki, Kazuhiro
• Format: Journal Article
• Language: English
• Published: United States 31.03.2023
• Subjects: Animals; Autoimmune Diseases; Autoimmunity; Immunity, Humoral; Mice; Pentacyclic Triterpenes
• DOI: 10.1126/sciimmunol.adc9324

Celastrol, a bioactive molecule extracted from the plant, has been shown to exhibit anti-inflammatory properties. However, its mechanism of action has not been fully elucidated. Here, we show that celastrol suppresses humoral immune responses and autoimmunity by disabling a protein complex consisting of copper metabolism MURR1 domain-containing (COMMD) 3 and COMMD8 (COMMD3/8 complex), a signaling adaptor for chemoattractant receptors. Having demonstrated the involvement of the COMMD3/8 complex in a mouse model of rheumatoid arthritis, we identified celastrol as a compound that covalently bound to and dissociated the COMMD3/8 complex. Celastrol inhibited B cell migration, reduced antibody responses, and blocked arthritis progression, recapitulating deficiency of the COMMD3/8 complex. These effects of celastrol were abolished in mice expressing a celastrol-resistant mutant of the COMMD3/8 complex. These findings establish that celastrol exerts immunosuppressive activity by targeting the COMMD3/8 complex. Our study suggests that the COMMD3/8 complex is a potentially druggable target in autoimmune diseases and points to celastrol as a lead pharmacologic candidate in this capacity.