title: TRPM2 regulates TXNIP-mediated NLRP3 inflammasome activation via interaction with p47 phox under high glucose in human monocytic cells.
abstract: Excessive production of reactive oxygen species (ROS) induced by hyperglycemia increased the secretion of interleukin-1β (IL-1β), which contributes to the pathogenesis of diabetes and its complications. Although high glucose (HG)-induced oxidative stress and aberrant Ca2+channels activity causes an increase in transmembrane Ca2+influx, however the relative contribution of Transient receptor potential (TRP) channels is not well studied. Here, we identified that HG (30 mM glucose for 48 h) induced the activation of the NLRP3-ASC inflammasome, leading to caspase-1 activation, and IL-1β and IL-18 secretion in human monocytic cell lines. Moreover, we used a hyperglycemia model in U937 monocytes, showing that the activation of TRPM2 was augmented, and TRPM2-mediated Ca2+influx was critical for NLRP3 inflammasome activation. This pathway involved NADPH oxidase-dependent ROS production and TXNIP-NLRP3 inflammasome pathway. Furthermore, the inhibition of TRPM2 reduced ROS production and lowered NADPH oxidase activity via cooperatively interaction with p47 phox in response to HG. These results provided a mechanistic linking between TRPM2-mediated Ca2+influx and p47 phox signaling to induce excess ROS production and TXNIP-mediated NLRP3 inflammasome activation under HG, and suggested that TRPM2 represented a potential target for alleviating NLRP3 inflammasome activation related to hyperglycemia-induced oxidative stress in Type 2 diabetes Mellitus (T2DM).
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, China.
authors.forename: Hisa Hui Ling
authors.initials: HH
authors.lastname: Tseng
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, China.
authors.forename: Chi Teng
authors.initials: CT
authors.lastname: Vong
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China.
authors.forename: Yiu Wa
authors.initials: YW
authors.lastname: Kwan
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, China.
authors.forename: Simon Ming-Yuen
authors.initials: SM
authors.lastname: Lee
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, China.
authors.forename: Maggie Pui Man
authors.initials: MP
authors.lastname: Hoi
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism; D058847:Inflammasomes / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008954:Models, Biological; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D050053:TRPM Cation Channels / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; C000589760:IL18 protein, human; C508585:IL1B protein, human; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D017382:Reactive Oxygen Species; D050053:TRPM Cation Channels; C121934:TRPM2 protein, human; C486715:TXNIP protein, human; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D020170:Caspase 1; D005947:Glucose