Dimethyl fumarate inhibits necroptosis and alleviates systemic inflammatory response syndrome by blocking the RIPK1-RIPK3-MLKL axis.

Abstract

Necroptosis has been implicated in various inflammatory diseases including tumor-necrosis factor-α (TNF-α)-induced systemic inflammatory response syndrome (SIRS). Dimethyl fumarate (DMF), a first-line drug for treating relapsing-remitting multiple sclerosis (RRMS), has been shown to be effective against various inflammatory diseases. However, it is still unclear whether DMF can inhibit necroptosis and confer protection against SIRS. In this study, we found that DMF significantly inhibited necroptotic cell death in macrophages induced by different necroptotic stimulations. Both the autophosphorylation of receptor-interacting serine/threonine kinase 1 (RIPK1) and RIPK3 and the downstream phosphorylation and oligomerization of MLKL were robustly suppressed by DMF. Accompanying the suppression of necroptotic signaling, DMF blocked the mitochondrial reverse electron transport (RET) induced by necroptotic stimulation, which was associated with its electrophilic property. Several well-known anti-RET reagents also markedly inhibited the activation of the RIPK1-RIPK3-MLKL axis accompanied by decreased necrotic cell death, indicating a critical role of RET in necroptotic signaling. DMF and other anti-RET reagents suppressed the ubiquitination of RIPK1 and RIPK3, and they attenuated the formation of necrosome. Moreover, oral administration of DMF significantly alleviated the severity of TNF-α-induced SIRS in mice. Consistent with this, DMF mitigated TNF-α-induced cecal, uterine, and lung damage accompanied by diminished RIPK3-MLKL signaling. Collectively, DMF represents a new necroptosis inhibitor that suppresses the RIPK1-RIPK3-MLKL axis through blocking mitochondrial RET. Our study highlights DMF's potential therapeutic applications for treating SIRS-associated diseases.

• Authors: Fu-Li Shi, Li-Sha Yuan, Tak-Sui Wong, Qing Li, Ya-Ping Li, Rong Xu, Yi-Ping You, Tao Yuan, Hong-Rui Zhang, Zi-Jian Shi, Qing-Bing Zha, Bo Hu, Xian-Hui He, Dong-Yun Ouyang
• Journal: Pharmacological research (Pharmacol Res) Vol. 189 Pg. 106697 (03 2023) ISSN: 1096-1186 [Electronic] Netherlands
• PMID: 36796462 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.

Chemical References

• Tumor Necrosis Factor-alpha
• Protein Kinases
• Dimethyl Fumarate
• Receptor-Interacting Protein Serine-Threonine Kinases
• Ripk3 protein, mouse
• Ripk1 protein, mouse
• MLKL protein, mouse

Topics

• Mice
• Animals
• Tumor Necrosis Factor-alpha (metabolism)
• Protein Kinases (metabolism)
• Dimethyl Fumarate
• Necroptosis
• Receptor-Interacting Protein Serine-Threonine Kinases (metabolism)
• Systemic Inflammatory Response Syndrome
• Oxidative Phosphorylation
• Apoptosis