Chalcones Display Anti-NLRP3 Inflammasome Activity in Macrophages through Inhibition of Both Priming and Activation Steps—Structure-Activity-Relationship and Mechanism Studies

Abstract

Chalcones are responsible for biological activity throughout fruits, vegetables, and medicinal plants in preventing and treating a variety of inflammation-related diseases. However, their structure-activity relationship (SAR) in inhibiting inflammasome activation has not been explored. We synthesized numerous chalcones and determined their SAR on lipopolysaccharide (LPS)-primed ATP-induced NLRP3 inflammasome activation. 11Cha1 displayed good inhibitory activity on release reaction of caspase-1, IL-1β, and IL-18. It significantly inhibited LPS-induced phosphorylation and proteolytic degradation of IĸB-α and nuclear translocation of NF-ĸB, but had little effect on mitogen-activated protein kinases (MAPKs) activities. Furthermore, 11Cha1 blocked LPS-induced up-regulation of NLRP3, pro-caspase-1, ASC, IL-18, and IL-1β, indicating the suppression on priming step of inflammasome activation. ASC dimerization and oligomerization are considered to be direct evidence for inflammasome activation. 11Cha1 profoundly inhibited ATP-induced formation of ASC dimers, trimers, and oligomers, and the assembly of ASC, pro-caspase-1, and NLRP3 in inflammasome formation. Decrease of intracellular K+ levels is the common cellular activity elicited by all NLRP3 inflammasome activators. 11Cha1 substantially diminished ATP-mediated K+ efflux, confirming the anti-NLRP3 inflammasome activity of 11Cha1. In summary, the SAR of chalcone derivatives in anti-inflammasome activities was examined. Besides, 11Cha1 inhibited both priming and activation steps of NLRP3 inflammasome activation. It inhibited NF-ĸB activation and subsequently suppressed the up-regulation of NLRP3 inflammasome components including NLRP3, ASC, pro-caspase-1, pro-IL-18, and pro-IL-1β. Next, 11Cha1 blocked ATP-mediated K+ efflux and suppressed the assembly and activation of NLRP3 inflammasome, leading to the inhibition of caspase-1 activation and proteolytic cleavage, maturation, and secretion of IL-1β and IL-18.

JC2-11, a benzylideneacetophenone derivative, attenuates inflammasome activation

“…In addition, the chalcone analog screened by the hit-to-lead attenuated the symptoms in the NLRP3 inflammasome-mediating diseases models, such as dextran sulfate sodium-induced colitis and LPS-induced sepsis 20 . Several chalcone analogs were synthesized and screened by the structure–activity relationship for the potent NLRP3 inhibitor 16 . 11Cha1, a selected analog, induced the proteolytic degradation of IκBα and the nuclear translocation of NF-κB.…”

“…11Cha1, a selected analog, induced the proteolytic degradation of IκBα and the nuclear translocation of NF-κB. In addition, it attenuated NLRP3 inflammasome by inhibiting K + efflux 16 . In addition, chalcone analogs were screened to pick up an NLRP3 inhibitor using Helicobacter pylori -infected macrophages 15 .…”

Inhibitors of the NLRP3 inflammasome pathway as promising therapeutic candidates for inflammatory diseases (Review)

“…The K + efflux is an upstream signaling event that causes NLRP3 inflammasome activation ( 128 ). The inflammasome activators that trigger NLRP3 inflammasome reduce the intracellular K + levels ( 129 ). ATP, a P2X7 purinoceptor agonist, induces a significant K + efflux in LPS-primed cells, which is substantially diminished by 11Cha1, a chalcone derivative.…”

Chronic kidney disease and NLRP3 inflammasome: Pathogenesis, development and targeted therapeutic strategies

“…Treating macrophages with CA-074-Me, a chemical inhibitor of cathepsin B, suppresses the inflammasome activation. Interestingly, the activation is absent when stimulating cathepsin B-deficient macrophages with particulates [ 46 ], indicating that inhibiting the inflammasome by the cathepsin B inhibitor may be due to a non-target effect or redundancy among cathepsin family members. In addition, siRNA- and shRNA-mediated knockdown of cathepsin B can promote the maturation of caspase-1 [ 47 , 48 ].…”