Quercetin Inhibits Inflammasome Activation by Interfering with ASC Oligomerization and Prevents Interleukin-1 Mediated Mouse Vasculitis.
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.
Department of Pathology, Center of Biological Science, Londrina State University, Londrina, Paraná, Brazil.|Department of Pediatric, Infectious diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Talita P
TP
Domiciano
Department of Pediatric, Infectious diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Daiko
D
Wakita
Division of Pulmonary and Critical Care Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Heather D
HD
Jones
Department of Pediatric, Infectious diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Timothy R
TR
Crother
Department of Pathology, Center of Biological Science, Londrina State University, Londrina, Paraná, Brazil.
Waldiceu A
WA
Verri
Department of Pediatric, Infectious diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Moshe
M
Arditi
Department of Pediatric, Infectious diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Kenichi
K
Shimada
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001014:Aortic Aneurysm / Q000473:pathology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy; D053468:CARD Signaling Adaptor Proteins / Q000737:chemistry / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D003331:Coronary Vessels / Q000473:pathology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors; D004195:Disease Models, Animal; D058847:Inflammasomes / Q000037:antagonists & inhibitors*; D053583:Interleukin-1beta / Q000378:metabolism*; D051379:Mice; D009080:Mucocutaneous Lymph Node Syndrome / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000037:antagonists & inhibitors; D055503:Protein Multimerization / Q000187:drug effects*; D011794:Quercetin / Q000494:pharmacology*; D014657:Vasculitis / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control
C540422:Aim2 protein, mouse; D000893:Anti-Inflammatory Agents; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; C512299:Ipaf protein, mouse; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C498534:Pycard protein, mouse; D011794:Quercetin