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-1? (IL-1?), 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-1? 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).

SUBMITTER: Tseng HH 

PROVIDER: S-EPMC5059733 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature