1. Cf‐02, a novel benzamide‐linked small molecule, blunts NF‐κB activation and NLRP3 inflammasome assembly and improves acute onset of accelerated and severe lupus nephritis in mice
- Author
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Yu Ling Tsai, Chung Yao Wu, Hsu Shan Huang, Yu-Juei Hsu, Kuo Feng Hua, Chih Yu Yang, Chih Yu Hsieh, Jia Feng Chan, Ann Chen, Chia-Chao Wu, Chia Chung Lee, Feng Cheng Liu, Chih Jun Wan, Debabrata Mukhopadhyay, Shuk-Man Ka, Jui Chun Weng, and Shin Ruen Yang
- Subjects
T cell ,Interleukin-1beta ,Lupus nephritis ,Priming (immunology) ,Biochemistry ,Article ,Mice ,chemistry.chemical_compound ,NLR Family, Pyrin Domain-Containing 3 Protein ,Autophagy ,Genetics ,medicine ,Animals ,Humans ,Immunologic Factors ,Secretion ,Benzamide ,Molecular Biology ,Cells, Cultured ,Chemistry ,Macrophages ,NF-kappa B ,Inflammasome ,Dendritic Cells ,medicine.disease ,Lupus Nephritis ,Small molecule ,Mice, Inbred C57BL ,Sjogren's Syndrome ,medicine.anatomical_structure ,Case-Control Studies ,Cancer research ,Female ,Biotechnology ,medicine.drug - Abstract
In the present study, acute onset of severe lupus nephritis was successfully treated in mice using a new, benzamide-linked, small molecule that targets immune modulation and the NLRP3 inflammasome. Specifically, 6-(2,4-difluorophenyl)-3-(3-(trifluoromethyl)phenyl)-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (Cf-02) (a) reduced serum levels of IgG anti-dsDNA, IL-1β, IL-6, and TNF-α, (b) inhibited activation of dendritic cells and differentially regulated T cell functions, and (c) suppressed the NF-κB/NLRP3 inflammasome axis, targeting priming and activating signals of the inflammasome. Moreover, treatment with Cf-02 significantly inhibited secretion of IL-1β in lipopolysaccharide-stimulated macrophages, but this effect was abolished by autophagy induction. These results recommend Cf-02 as a promising drug candidate for the serious renal conditions associated with systemic lupus erythematosus. Future investigations should examine whether Cf-02 may also be therapeutic in other types of chronic kidney disease involving NLRP3 inflammasome-driven signaling.
- Published
- 2021