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.

Leptin promotes IL-18 secretion by activating the NLRP3 inflammasome in RAW 264.7 cells

“…The present study revealed that leptin promotes IL-18 secretion by increasing ROS synthesis and K + efflux, which may activate the NLRP3 inflammasome in RAW 264.7 cells. Numerous studies have indicated that ROS and K + efflux may serve as strong activators for the NLRP3 inflammasome (36,37).…”

Metabolic regulation of NLRP3

“…In human monocytes, Ugonin U stimulated NLRP3 activation by triggering mitochondrial ROS generation. Ugonin U‐mediated activation of PLC was found to trigger release of intracellular calcium (Ca 2+ ), and negative targeting of Ca 2+ release inhibited the inflammatory effects of Ugonin U . Furthermore, scavenging of mitochondrial ROS by the tool compound MitoTEMPO limited the effects of Ugonin U, firmly placing mitochondrial ROS as a determinant in NLRP3 inflammasome activation.…”

“…Ugonin U-mediated activation of PLC was found to trigger release of intracellular calcium (Ca 2+ ), and negative targeting of Ca 2+ release inhibited the inflammatory effects of Ugonin U. 30 and IL1β transcription, linking fatty acid synthesis as a key driver of both inflammatory gene transcription and NLRP3 activation. 31 In a separate and somewhat contradicting study, Moon et al also identified the ROS producer NADPH Oxidase 4 (NOX4), an enzyme involved in superoxide anion formation, as an NLRP3 activator through fatty acid oxidation.…”

Antidiabetic Constituents from Helminthostachys zeylanica (L) Hook (Ophioglossaceae)

“…6 Ugonin U possessed immunomodulator effect on human neutrophils. 10 Nevertheless, the antidiabetic activity from H. zeylanica has never been reported previously. Therefore, the objective of this study was to assess the α-glucosidase inhibitory activity of the secondary metabolites from H. zeylanica roots.…”