title: Chemical probing reveals insights into the signaling mechanism of inflammasome activation.
abstract: Caspase-1-mediated IL-1β production is generally controlled by two pathways. Toll-like receptors (TLRs) recognize pathogen-derived products and induce NF-κB-dependent pro-IL-1β transcription; NOD-like receptors (NLRs) assemble caspase-1-activating inflammasome complexes that sense bacterial products/danger signals. Through a targeted chemical screen, we identify bromoxone, a marine natural product, as a specific and potent inhibitor of the caspase-1 pathway. Bromoxone is effective over diverse inflammatory stimuli including TLR ligands plus ATP/nigericin, cytosolic DNA, flagellin and Bacillus anthracis lethal toxin. Bromoxone also efficiently suppresses caspase-1 activation triggered by several types of bacterial infection. Bromoxone acts upstream or at the level of the inflammasome in a transcription-independent manner. Bromoxone also inhibits pro-IL-1β expression by targeting components upstream of IKK in the TLR-NF-κB pathway. The unique dual activities of bromoxone are shared by the known TAK1 inhibitor that specifically blocks Nalp3 inflammasome activation. Hinted from the mechanistic and pharmacological properties of bromoxone, we further discover that several known NF-κB inhibitors that act upstream of IKK, but not those targeting IKK or IKK downstream, are potent blockers of different NLRs-mediated caspase-1 activation. Our study uncovers a possible non-transcriptional molecular link between the NLR (Nalp3)-mediated inflammasome pathway and TLR-NF-κB signaling, and suggests a potential strategy to develop new anti-inflammatory drugs.
authors.affiliation: College of Life Sciences, Beijing Normal University, Beijing 100875, China.
authors.forename: Yi-Nan
authors.initials: YN
authors.lastname: Gong
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Wang
authors.forename: Jiayi
authors.initials: J
authors.lastname: Wang
authors.forename: Zhenxiao
authors.initials: Z
authors.lastname: Yang
authors.forename: Shan
authors.initials: S
authors.lastname: Li
authors.forename: Jieling
authors.initials: J
authors.lastname: Yang
authors.forename: Liping
authors.initials: L
authors.lastname: Liu
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Lei
authors.forename: Feng
authors.initials: F
authors.lastname: Shao
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000494:pharmacology*; D020170:Caspase 1 / Q000378:metabolism; D061945:Caspase Inhibitors; D002460:Cell Line; D004852:Epoxy Compounds / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D061945:Caspase Inhibitors; D004852:Epoxy Compounds; D058847:Inflammasomes; D053583:Interleukin-1beta; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D051193:Toll-Like Receptors; C415026:bromoxone; D051550:I-kappa B Kinase; D020170:Caspase 1