Identification of a Small Molecule with Strong Anti-Inflammatory Activity in Experimental Autoimmune Encephalomyelitis and Sepsis through Blocking Gasdermin D Activation

上睑下垂 实验性自身免疫性脑脊髓炎 炎症体 炎症 化学 免疫学 细胞生物学 医学 生物
作者
Runjing Cao,Zihao Li,Chuyu Wu,Senlin Ji,Yahui Li,Xiang Cao,Xiaohong Dong,Meiling Jiang,Tao Pang,Chenhui Wang,Jingwei Li,Yun Xu,Cun-Jin Zhang
出处
期刊:Journal of Immunology [The American Association of Immunologists]
卷期号:209 (4): 820-828 被引量:8
标识
DOI:10.4049/jimmunol.2100977
摘要

Abstract Pyroptosis is a key inflammatory form of cell death participating in the progression of many inflammatory diseases, such as experimental autoimmune encephalomyelitis (EAE) and sepsis. Identification of small molecules to inhibit pyroptosis is emerging as an attractive strategy. In this study, we performed a screening based on in silico docking of compounds on the reported Gasdermin D (GSDMD) three-dimensional structure and found C202-2729 demonstrated strong anti-inflammatory effects in both endotoxin shock and EAE mouse models. Oral administration of C202-2729 was capable of attenuating EAE disease severity significantly and has the comparable effects to teriflunomide, the first-line clinical drug of multiple sclerosis. We found C202-2729 remarkably suppressed macrophage and T cell–associated immune inflammation. Mechanistically, C202-2729 neither impact GSDMD cleavage nor the upstream inflammasome activation in mouse immortalized bone marrow–derived macrophages. However, C202-2729 exposure significantly repressed the IL-1β secretion and cell pyroptosis. We found C202-2729 directly bonds to the N terminus of GSDMD and blocks the migration of the N-terminal GSDMD fragment to cell membrane, restraining the pore-forming and mature IL-1β release. Collectively, our findings provide a new molecule with the potential for translational application in GSDMD-associated inflammatory diseases.
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