Scutellarin inhibits caspase-11 activation and pyroptosis in macrophages via regulating PKA signaling

• 来源期刊: 药学学报（英文版）
• 年，卷（期）: 2021,（1）
• 所属期刊栏目: Original articles
• 页码范围: 112-126
• 页数: 15页
• 语种: 英文

摘要

Inflammatory caspase-l1 senses and is activated by intracellular lipopolysaccharide(LPS)leading to pyroptosis that has critical role in defensing against bacterial infection,whereas its excess acti-vation under pathogenic circumstances may cause various inflammatory diseases.However,there are few known drugs that can control caspase-11 activation.We report here that scutellarin,a flavonoid from Erigeron breviscapus,acted as an inhibitor for caspase-11 activation in macrophages.Scutellarin dose-dependently inhibited intracellular LPS-induced release of caspase-1 lp26(indicative of caspase-11 acti-vation)and generation of N-terminal fragment of gasdermin D(GSDMD-NT),leading to reduced pyrop-tosis.It also suppressed the activation of non-canonical nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3(NLRP3)inflammasome as evidenced by reduced apoptosis-associated speck-like protein containing a CARD(ASC)speck formation and decreased interleukin-1 beta(IL-1/)and caspase-lplO secretion,whereas the NLRP3-specific inhibitor MCC950 only inhibited IL-1/8 and caspase-lp10 release and ASC speck formation but not pyroptosis.Scutellarin also suppressed LPS-induced caspase-11 activation and pyroptosis in RAW 264.7 cells lacking ASC expression.More-over,scutellarin treatment increased Ser/Thr phosphorylation of caspase-l1 at protein kinase A(PKA)-specific sites,and its inhibitory action on caspase-11 activation was largely abrogated by PKA inhibitor H89 or by adenylyl cyclase inhibitor MDL12330A.Collectively,our data indicate that scutel-larin inhibited caspase-11 activation and pyroptosis in macrophages at least partly via regulating the PKA signaling pathway.