Thioredoxin-interacting protein links oxidative stress to inflammasome activation

 Rongbin Zhou et al. Nature immunology 11: 136-140 (2010)

Student:  Huo-Sheng Chiou (邱穫升)                                    Time: 15:00~16:00, Jun. 2, 2010

Commentator: Dr. Yee-Shin Lin (林以行 博士)                 Place: Room 601

Abstract

Inflammasomes are molecular platforms that can be activated when host cells suffering from cellular infection or environment stress. Activation of inflammasomes triggers the maturation of proinflammatory cytokines such as interleukin-1b to engage innate immune defenses. Among the inflammasomes, NLRP3 inflammasome is the most characterized and it is activated by many irritants from pathogens, environment, and host-derived molecules. All of above activators are associated with reactive oxygen species (ROS) generation. Although ROS and low cytoplasmic concentrations of potassium (K⁺) are known to be essential for activation of NLRP3 inflammasome, the signaling pathways still need to be clarified. In this study, the authors use the yeast two-hybrid screen to identify thioredoxin-interacting protein (TXNIP) as a binding partner of NLRP3. TXNIP is known to be a Thioredoxin (TRX) binding protein that regulates the antioxidant function of TRX. Therefore, the correlation with ROS stress between TXNIP and NLRP3 inflammasome become an interesting question to be answered. At first, the authors confirm directly binding between NLRP3 and TXNIP both in HEK293 and THP-1 macrophage cell lines. Furthermore, the results of immunoprecipitation and immunoblot analysis show that TXNIP is essential for activation of NLRP3 inflammasome through ROS stimulation in vitro and ex vivo. Under oxidative stress, TXNIP is released from reduced TRX and then binds with NLRP3 in THP-1 cells. On the other hand, the author shows that TXNIP^-/- and NLRP3^-/- mice have less IL-1b production. Taken together, TXNIP induces IL-1b production through NLRP3 inflammasome activation when it disassociates from TXNIP-TRX complex under ROS stress. Recently, inflammasome-generated IL-1b is thought to link with insulin tolerance and type 2 diabetes (T2D). The authors discover the hyperglycemia situation that induce TXNIP expression and IL-1b production ex vivo and in vivo. In agreement with that, NLRP3^-/- mice have greater glucose and insulin tolerance. Although the connection between TXNIP, inflammasome, and IL-1b still needs to identify. The authors provide a hypothesis for progression of T2D.

References

1.      Kate S. et al. The inflammasomes Cell 140: 821-832(2010)

2. Ahsan M. K. et al. Thioredoxin and thioredoxin-binding protein-2 in cancer and metabolic syndrome. Free Radical Biology & Medicine 43: 861-868(2007)