JC2-11, a benzylideneacetophenone derivative, attenuates inflammasome activation

• Published in: Scientific reports Vol. 12; no. 1; p. 22484
• Main Authors: Lee, Gilyoung, Ahn, Huijeong, Yun, Jang-Hyuk, Park, Jeongho, Lee, Eunsong, Oh, Seikwan, Lee, Geun-Shik
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.12.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 631/250/256; 631/250/262; Adenosine triphosphate; Animals; Antioxidants; Caspase 1 - metabolism; Caspase-1; Chalcone - pharmacology; Cytokines; Dehydrogenases; Drug dosages; Flavonoids; Humanities and Social Sciences; Humans; IL-1β; Inflammasomes; Inflammasomes - metabolism; Interleukin-1beta - metabolism; Lactic acid; Lipopolysaccharides; Lipopolysaccharides - metabolism; Lipopolysaccharides - pharmacology; Macrophages; Macrophages - metabolism; Metabolic disorders; Metabolism; Mice; Mitochondria; multidisciplinary; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Proteins; Reactive oxygen species; Science; Science (multidisciplinary); Sepsis; Veterinary medicine
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-27129-3

Dysregulation of inflammasome activation induces chronic and excess inflammation resulting in several disorders, such as metabolic disorders and cancers. Thus, screening for its regulator derived from natural materials has been conducted progressively. JC2-11 (JC) was designed to enhance the antioxidant activity based on a chalcone, which is abundant in edible plants and a precursor of flavonoids. This study examined the effects of JC on inflammasome activation in human and murine macrophages. JC inhibited the secretion of interleukin (IL)-1β and lactate dehydrogenases, and the cleavage of caspase-1 and gasdermin D in response to the tested activators (i.e., NLRP3, NLRC4, AIM2, and non-canonical inflammasome triggers). In addition, JC attenuated IL-1β secretion from lipopolysaccharide (LPS)-injected mice, an inflammasome-mediating disease model. Mechanistically, JC blocked the expression of the inflammasome components during the priming step of the inflammasome, and interrupted the production of mitochondrial reactive oxygen species. In addition, JC inhibited the activity of caspase-1. In conclusion, JC may be a candidate pan-inflammasome inhibitor.