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).

Hyperosmotic Stress–Induced TRPM2 Channel Activation Stimulates NLRP3 Inflammasome Activity in Primary Human Corneal Epithelial Cells

“…40 It was suggested that in type 2 diabetes mellitus, TRPM2 channels are a potential target for alleviating NLRP3 inflammasome activation stemming from hyperglycemia-induced oxidative stress. 41 Our results suggest that the inflammatory conditions associated with some ocular surface diseases in some cases may stem from TRPM2 activation because the osmotic stress we imposed is comparable to the tear film osmolarity of clinical samples obtained from some individuals afflicted with DE disease. Furthermore, in other studies involving different groups of DE patients, their ROS levels were elevated in the ocular surface tissues.…”

Stressing out the mitochondria: Mechanistic insights into NLRP3 inflammasome activation

“…The correlation between oxidative stress, TXNIP activity and NLRP3 was first made following the discovery that TXNIP binds to NLRP3, using a yeast two‐hybrid screen . Subsequently, ER stressors (e.g., thapsigargin) and/or high glucose have been suggested to trigger NLRP3 inflammasome activation in islets, adipose tissue/adipocytes, macrophage and monocytes in a TXNIP‐dependent manner (see Section 4.2.2 for ambiguities surrounding TXNIP involvement in NLRP3 activation). It is worth noting that there are discrepancies between mouse and human as to whether β‐cells have a functional NLRP3 inflammasome .…”

The Impact of Acute Ingestion of a Ketone Monoester Drink on LPS-Stimulated NLRP3 Activation in Humans with Obesity

“…For example, Maedler and colleagues found that pancreatic beta-cells cultured in high glucose upregulate IL-1β secretion [6]. Exposure of human monocytes to high glucose causes activation of the NLRP3 inflammasome and promotes release of IL-1β and IL-18 [7,8]. Furthermore, activation of NLRP3 has been shown to be critical to the development of obesity-induced insulin resistance in mice and humans [9].…”

“…Ketone bodies, with their ability to act as immunomodulatory signaling metabolites [6][7][8][9], hold potential to slow progression of obesity-related diseases. Specifically, the ketone body β-hydroxybutyrate (β-OHB) has been shown to block activation of pro-caspase-1 into caspase-1, and consequently attenuate formation of mature IL-1β in stimulated mouse and human leukocytes [10][11][12] in an NLRP3 inflammasome-specific manner [13].…”