title: Ugonin U stimulates NLRP3 inflammasome activation and enhances inflammasome-mediated pathogen clearance.
abstract: The NOD-like receptor pyrin domain 3 (NLRP3) inflammasome contains Nod-like receptors, a subclass of pattern recognition receptors, suggesting that this complex has a prominent role in host defenses. Various structurally diverse stimulators activate the NLRP3 inflammasome through different signaling pathways. We previously reported that ugonin U (UgU), a natural flavonoid isolated from Helminthostachys zeylanica (L) Hook, directly stimulates phospholipase C (PLC) and triggers superoxide release in human neutrophils. In the present study, we showed that UgU induced NLRP3 inflammasome assembly and subsequent caspase-1 and interleukin (IL)-1β processing in lipopolysaccharide-primed human monocytes. Moreover, UgU elicited mitochondrial superoxide generation in a dose-dependent manner, and a specific scavenger of mitochondrial reactive oxygen species (ROS) diminished UgU-induced IL-1β and caspase-1 activation. UgU induced Ca2+mobilization, which was inhibited by treatment with inhibitors of PLC or inositol triphosphate receptor (IP3R). Blocking Ca2+mobilization, PLC, or IP3R diminished UgU-induced IL-1β release, caspase-1 activation, and mitochondrial ROS generation. These data demonstrated that UgU activated the NLPR3 inflammasome activation through Ca2+mobilization and the production of mitochondrial ROS. We also demonstrated that UgU-dependent NLRP3 inflammasome activation enhanced the bactericidal function of human monocytes. The ability of UgU to stimulate human neutrophils and monocytes, both of which are professional phagocytes, and its capacity to activate the NLRP3 inflammasome, which is a promising molecular target for developing anti-infective medicine, indicate that UgU treatment should be considered as a possible novel therapy for treating infectious diseases.
authors.affiliation: Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan.
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.
authors.forename: Chuan-Hui
authors.initials: CH
authors.lastname: Yang
authors.affiliation: Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan.
authors.forename: Yung-Fong
authors.initials: YF
authors.lastname: Tsai
authors.affiliation: Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 804, Taiwan.
authors.forename: Chih-Chuang
authors.initials: CC
authors.lastname: Liaw
authors.affiliation: Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Taoyuan 333, Taiwan.
authors.forename: Wen-Yi
authors.initials: WY
authors.lastname: Chang
authors.affiliation: Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Taoyuan 333, Taiwan; Research Center for Industry of Human Ecology, Research Center for Chinese Herbal Medicine, and Graduate Institute of Health Industry Technology, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan. Electronic address: htl@mail.cgu.edu.tw.
authors.forename: Tsong-Long
authors.initials: TL
authors.lastname: Hwang
mesh_terms: D000893:Anti-Inflammatory Agents / Q000302:isolation & purification / Q000494:pharmacology*; D000975:Antioxidants / Q000302:isolation & purification / Q000494:pharmacology*; D002118:Calcium / Q000276:immunology / Q000378:metabolism; D020170:Caspase 1 / Q000235:genetics / Q000276:immunology; D029624:Ferns / Q000737:chemistry; D005419:Flavonoids / Q000302:isolation & purification / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006801:Humans; D058847:Inflammasomes / Q000187:drug effects* / Q000276:immunology; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000276:immunology; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D008928:Mitochondria / Q000187:drug effects / Q000276:immunology; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology / Q000382:microbiology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000819:agonists* / Q000235:genetics / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D061251:Primary Cell Culture; D027343:Rhizome / Q000737:chemistry; D013211:Staphylococcus aureus / Q000254:growth & development / Q000276:immunology; D013481:Superoxides / Q000276:immunology / Q000378:metabolism; D000074084:THP-1 Cells; D010738:Type C Phospholipases / Q000235:genetics / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D005419:Flavonoids; C508585:IL1B protein, human; D058847:Inflammasomes; D053496:Inositol 1,4,5-Trisphosphate Receptors; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C000624824:ugonin U; D013481:Superoxides; D010738:Type C Phospholipases; D020170:Caspase 1; D002118:Calcium
keywords: Inflammasome; Innate immunity; Monocyte; NLRP3; Ugonin U