Abstract
Interleukin-1β (IL-1β) is a highly inflammatory cytokine that significantly contributes to both acute and chronic inflammatory diseases. The secretion of IL-1β requires a unique protease, caspase-1, which is activated by various protein platforms called inflammasomes. Data suggests a key role for mitochondrial reactive oxygen species for inflammasome activation. Flavonoids constitute a group of naturally occurring polyphenolic molecules with many biological activities, including antioxidant effects. In this study, we investigated the effect of three flavonoids, quercetin (QUC), naringenin, and silymarim on inflammasome activation. We found that QUC inhibits IL-1β secretion by both the NLRP3 and AIM2 inflammasome in a dose dependent manner, but not the NLRC4 inflammasome. QUC inhibition of the inflammasome was still observed in Atg16l1 knockout macrophages, indicating that QUC’s effect was autophagy independent. Since QUC inhibited both NLRP3 and AIM2 inflammasomes but not NLRC4, we assessed ASC speck formation. QUC reduced ASC speck formation and ASC oligomerization compared with controls. Additionally, QUC inhibited IL-1β in Cryopyrin-Associated Periodic Syndromes (CAPS) macrophages, where NLRP3 inflammasome is constitutively activated. In conclusion, QUC inhibits both the NLRP3 and AIM2 inflammasome by preventing ASC oligomerization and may be a potential therapeutic candidate for Kawasaki disease vasculitis and other IL-1 mediated inflammatory diseases.
Highlights
Kawasaki disease is a multisystem acute vasculitis that primarily affects young children and is the most common acquired cardiovascular disease among children in developed countries[6]
Our group has recently shown that NLRP3 inflammasome activation and IL-1βare critically important in the development of coronary arteritis and abdominal aorta aneurysms (AAA) and dilatations seen in an experimental Kawasaki disease vasculitis mouse model[1,11]
While it is already known that flavonoids can potentially inhibit NF-κB activation[19] thereby preventing proIL-1βand pro-caspase-1 synthesis, it is not known whether flavonoids could inhibit inflammasome activation by interfering with signal 2
Summary
Kawasaki disease is a multisystem acute vasculitis that primarily affects young children and is the most common acquired cardiovascular disease among children in developed countries[6]. Our group has recently shown that NLRP3 inflammasome activation and IL-1βare critically important in the development of coronary arteritis and abdominal aorta aneurysms (AAA) and dilatations seen in an experimental Kawasaki disease vasculitis mouse model[1,11]. Quercetin inhibits oxidative species generating enzymes such as xanthine oxidase, LOX, and nicotinamide adenine dinucleotide phosphate oxidase (NADPH)[12,13,14] It is a potent anti-cancer agent, exhibiting different activities such as cell cycle regulation, interaction with type II estrogen binding sites, and tyrosine kinase inhibition[15]. In this study we focused on the immuno-pharmacologic mechanism of these flavonoids on inflammasome activated macrophages in vitro, as well as and a bacterial cell wall extract induced coronary arteritis and abdominal aorta aneurysm. We report that quercetin inhibited inflammasome activity through inhibition of ASC oligomerization in vitro and quercetin treatment was beneficial in preventing vascular inflammation in the KD vasculitis mouse model, which is an IL-1-dependent experimental model
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