Inflammatory caspase-11 senses and is activated by intracellular lipopolysaccharide(LPS)leading to pyroptosis that has critical role in defensing against bacterial infection,whereas its excess activation under pathoge...Inflammatory caspase-11 senses and is activated by intracellular lipopolysaccharide(LPS)leading to pyroptosis that has critical role in defensing against bacterial infection,whereas its excess activation 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 dosedependently inhibited intracellular LPS-induced release of caspase-11 p26(indicative of caspase-11 activation)and generation of N-terminal fragment of gasdermin D(GSDMD-NT),leading to reduced pyroptosis.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 apoptosisassociated speck-like protein containing a CARD(ASC)speck formation and decreased interleukin-1 beta(IL-1 b)and caspase-1 p10 secretion,whereas the NLRP3-specific inhibitor MCC950 only inhibited IL-1 b and caspase-1 p10 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.Moreover,scutellarin treatment increased Ser/Thr phosphorylation of caspase-11 at protein kinase A(PKA)-specific sites,and its inhibitory action on caspase-11 activation was largely abrogated by PKAinhibitor H89 or by adenylyl cyclase inhibitor MDL12330 A.Collectively,our data indicate that scutellarin inhibited caspase-11 activation and pyroptosis in macrophages at least partly via regulating the PKA signaling pathway.展开更多
基金supported by the National Natural Science Foundation of China(Nos.81773965,81873064,and 81673664)
文摘Inflammatory caspase-11 senses and is activated by intracellular lipopolysaccharide(LPS)leading to pyroptosis that has critical role in defensing against bacterial infection,whereas its excess activation 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 dosedependently inhibited intracellular LPS-induced release of caspase-11 p26(indicative of caspase-11 activation)and generation of N-terminal fragment of gasdermin D(GSDMD-NT),leading to reduced pyroptosis.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 apoptosisassociated speck-like protein containing a CARD(ASC)speck formation and decreased interleukin-1 beta(IL-1 b)and caspase-1 p10 secretion,whereas the NLRP3-specific inhibitor MCC950 only inhibited IL-1 b and caspase-1 p10 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.Moreover,scutellarin treatment increased Ser/Thr phosphorylation of caspase-11 at protein kinase A(PKA)-specific sites,and its inhibitory action on caspase-11 activation was largely abrogated by PKAinhibitor H89 or by adenylyl cyclase inhibitor MDL12330 A.Collectively,our data indicate that scutellarin inhibited caspase-11 activation and pyroptosis in macrophages at least partly via regulating the PKA signaling pathway.
