ABSTRACT
@#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 dose-dependently inhibited intracellular LPS-induced release of caspase-11p26 (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 apoptosis-associated speck-like protein containing a CARD (ASC) speck formation and decreased interleukin-1 beta (IL-1β) and caspase-1p10 secretion, whereas the NLRP3-specific inhibitor MCC950 only inhibited IL-1β and caspase-1p10 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 PKA inhibitor H89 or by adenylyl cyclase inhibitor MDL12330A. Collectively, our data indicate that scutellarin inhibited caspase-11 activation and pyroptosis in macrophages at least partly via regulating the PKA signaling pathway.
ABSTRACT
Inflammation is an immune response mediated by innate immune cells of tissues, against invading microbes and cellular stress. The hallmark of inflammatory responses is the activation of inflammasomes — multiprotein oligomers comprising intracellular pattern recognition receptors and inflammatory effectors — such as ASC and pro-cysteine-aspartic protease (pro-caspase)-1. Inflammasomes can be classified as canonical or non-canonical, and their activation in response to various ligands commonly induces caspase-1 activation and gasdermin D (GSDMD) processing, leading to caspase-1-mediated maturation and secretion of the pro-inflammatory cytokines IL-1β and IL-18, and GSDMD-mediated pyroptosis through pore generation in cell membranes. Although inflammation protects the host from harmful stimuli, chronic inflammation is a critical risk factor for inflammatory diseases, and several studies have investigated the role of canonical inflammasomes in inflammatory responses and diseases, with emerging studies focusing on the role of non-canonical inflammasomes. This review discusses recent studies on the regulatory roles of the caspase-11 non-canonical inflammasome in the pathogenesis of inflammatory diseases. Additionally, it provides an insight into the development of novel therapeutics based on targeting caspase-11 non-canonical inflammasome and its downstream effectors to prevent and treat human inflammatory conditions.
Subject(s)
Humans , Cell Membrane , Cytokines , Inflammasomes , Inflammation , Interleukin-18 , Ligands , Pyroptosis , Receptors, Pattern Recognition , Risk FactorsABSTRACT
Objective To investigate the effect of CCK-8 on CHOP/caspase-11/caspase-1 expressions induced by LPS in RAW264.7 cells.Methods RAW264.7 cells were incubated with LPS and/or CCK-8 and/or CCK-8 1R blocking agent devazepide for indicated times .CHOP and caspase-11 protein expressions were determined by West-ern blot , caspase-1 activity was analyzed by kit , IL-1βexpression level was analyzed by ELISA .Results Both CHOP and caspase-11 expression were upregulated in LPS-activated RAW264.7 cell, which were inhibited by pre-treatment of CCK-8 .Pre-treatment of devazepide inhibited the effects of CCK-8 significantly .The same effects were found in caspase-1 activity and IL-1βexpression .Conclusions CCK-8 exerts an anti-inflammatory effect by inhib-iting CHOP/caspase-11/caspase-1 expressions induced by LPS in RAW264.7 cell.CCK 1R may contribute to the anti-inflammatory effect of CCK-8.
ABSTRACT
Murine caspase-11 is orthologus to human caspase-4 and caspase-5, and is required for the response to cholera toxin B and infection with Escherichia coli, Citrobacter rodentium or Vibrio cholerae. Caspase-11 rather than caspase-1 is the main offender involved in sepsis. Hence, caspase-11 plays an essential pro-inflammatory role in innate immune response to bacterial infections.