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WP1130 relieves septic shock in mice by inhibiting NLRP3 inflammasome activation

Objective: To investigate the mechanism by which the small molecule compound WP1130 inhibits NLRP3 inflammasome activation and alleviates septic shock.

Methods: Mouse bone marrow-derived macrophages (BMDM) and human THP-1 cells were pre-treated with WP1130 before stimulation with different NLRP3 inflammasome agonists (Nigericin, ATP, MSU and intracellular LPS transfection), and AIM2 inflammasomes were activated with poly A: T. The levels of caspase-1 and IL-1β in the cell culture supernatant were determined using Western blotting and ELISA, and mitochondrial damage in the cells was observed using confocal microscopy. In the animal experiment, male C57BL/6 mice were randomized into blank control group, septic shock group (LPS group) and WP1130 treatment group (WP1130+LPS group), and the levels of IL-1β and TNF-α in the serum and peritoneal cavity were detected using ELISA.

Results: In murine BMDM and human THP-1 cells, WP1130 significantly inhibited NLRP3 agonists-induced caspase-1 and IL-1β secretion in a dose-dependent manner (P < 0.05) but did not obviously affect the secretion of such inflammatory factors as IL-6 and TNF-α that were not associated with inflammasomes (P>0.05). Treatment with WP1130 did not significantly affect poly A: T-induced activation of AIM2 inflammasomes (P>0.05) or induce obvious changes in mitochondrial damage, an upstream signal of NLRP3 inflammasome activation. In the mouse model of LPS-induced septic shock, WP1130 treatment significantly reduced the level of IL-1β (P < 0.05) without obviously affecting TNF-α level either in the serum or in the peritoneal cavity (P>0.05).

Conclusion: WP1130 specifically inhibits NLRP3 inflammasome activation to alleviate LPS-induced septic shock in mice.

Comments：

In summary, the study found that WP1130 inhibits NLRP3 inflammasome activation and alleviates septic shock both in vitro and in vivo. The mechanism of action appears to be specific to the NLRP3 inflammasome, as WP1130 did not affect the activation of AIM2 inflammasomes or the secretion of non-inflammasome-associated cytokines. Mitochondrial damage does not seem to be the target of WP1130, as it did not induce any significant changes in this upstream signal of NLRP3 activation. These findings suggest that WP1130 may be a promising therapeutic candidate for the treatment of inflammatory diseases associated with NLRP3 inflammasome activation.

Related Products

Cat.No. Product Name Information
S2243 Degrasyn (WP1130) Degrasyn (WP1130) is a selective deubiquitinase (DUB: USP5, UCH-L1, USP9x, USP14, and UCH37) inhibitor and also suppresses Bcr/Abl, also a JAK2 transducer (without affecting 20S proteasome) and activator of transcription (STAT). Degrasyn (WP1130) induces apoptosis and blocks autophagy.

Related Targets

Bcr-Abl DUB Autophagy Apoptosis related