Targeting Peroxiredoxin 1 by a Curcumin Analogue, AI-44, Inhibits NLRP3 Inflammasome Activation and Attenuates Lipopolysaccharide-Induced Sepsis in Mice.
Wen LiuWenjie GuoYongcheng ZhuShuang PengWei ZhengChao ZhangFenli ShaoYuyu ZhuNan HangLingdong KongXiangbao MengQiang XuYang SunPublished in: Journal of immunology (Baltimore, Md. : 1950) (2018)
Aberrant activation of the NLRP3 inflammasome contributes to the onset and progression of various inflammatory diseases, making it a highly desirable drug target. In this study, we screened a series of small compounds with anti-inflammatory activities and identified a novel NLRP3 inflammasome inhibitor, AI-44, a curcumin analogue that selectively inhibited signal 2 but not signal 1 of NLRP3 inflammasome activation. We demonstrated that AI-44 bound to peroxiredoxin 1 (PRDX1) and promoted the interaction of PRDX1 with pro-Caspase-1 (CASP1), which led to the suppression of association of pro-CASP1 and ASC. Consequently, the assembly of the NLRP3 inflammasome was interrupted, and the activation of CASP1 was inhibited. Knockdown of PRDX1 significantly abrogated the inhibitory effect of AI-44 on the NLRP3 inflammasome. Importantly, AI-44 alleviated LPS-induced endotoxemia in mice via suppressing NLRP3 inflammasome activation. Taken together, our work highlighted PRDX1 as a negative regulator of NLRP3 inflammasome activation and suggested AI-44 as a promising candidate compound for the treatment of sepsis or other NLRP3 inflammasome-driven diseases.
Keyphrases
- nlrp inflammasome
- artificial intelligence
- lps induced
- lipopolysaccharide induced
- anti inflammatory
- inflammatory response
- intensive care unit
- acute kidney injury
- type diabetes
- oxidative stress
- cell death
- transcription factor
- adipose tissue
- metabolic syndrome
- drug delivery
- combination therapy
- signaling pathway
- insulin resistance
- endoplasmic reticulum stress
- adverse drug
- smoking cessation
- drug induced