NLRP3 inflammasome inhibitor MCC950 attenuates primary dysmenorrhea in mice via the NF-\u03baB/COX-2/PG pathway

Biao Tang,Yu Liu,Dan Liu,Lingyu Chen

doi:10.1186/s12950-020-00251-7

Abstract

BackgroundPrimary dysmenorrhea (PD) constitutes a common gynecological disease among young women. The NLRP3 inflammasome may be activated and expressed in PD, but the mechanistic link between NLRP3 inflammasome activation and PD is still unclear.MethodsTo investigate the potential role of NLRP3 inflammasome activation in the pathogenesis of PD, 30 female Kunming mice without pregnancy were used for experiments. The PD mouse model was constructed by 11 days of successive co-treatment with estradiol and oxytocin. MCC950, a potent and specific small-molecule inhibitor of the NLRP3 inflammasome, was used to treat PD mice. The disease level was assessed by the writhing response and hot water tail-flick test. The levels of prostaglandin E2 (PGE2) and prostaglandin F2 alpha (PGF2α) in the uterine tissues of mice were detected by ELISA. The expression levels of protein and cytokines, including NLRP3, cysteine aspartic acid-specific protease 1 (caspase-1), interleukin (IL)-1β, IL-18, nuclear factor kappa B (NF-κB) p65, phospho-NF-κB p65, and cyclooxygenase-2 (COX-2) were revealed by western blot analysis.ResultsMCC950 greatly ameliorated the writhing response induced by the combination of oxytocin and estradiol, with an increasing length of tail-flick latency. MCC950 also significantly decreased the levels of PGF2α and PGE2, and the expressions of NLRP3, caspase-1, IL-1β, IL-18, phospho-NF-κB p65, NF-κB p65, and COX-2 in the uterus.ConclusionsMCC950 markedly alleviated the pain and pathological damage in PD mice by inhibiting NLRP3 activation. The underlying mechanism may be related to hypoactive uterine inflammation via suppression of NLRP3 activation and the NF-κB/COX-2/PG pathway in uteruses of PD mice.

Highlights

Primary dysmenorrhea (PD) constitutes a common gynecological disease among young women
Increasing studies have shown that the Nuclear factor kappa B (NF-κB)/COX2/PG pathway plays a pathogenic role in PD, which suggests that therapeutic interventions of the NF-κB/COX-2/ PG pathway can exert protective effects against PD [5, 6]
MCC950 inhibited the activation of nucleotidebinding oligomerization domain-like receptor protein 3 (NLRP3) inflammasomes in uterine tissues of mice with PD Uterine tissues were examined by western blotting to detect the levels of NLRP3, cleaved-caspase-1 (p20) and activated forms of IL-1β, and IL-18

Summary

Introduction

Primary dysmenorrhea (PD) constitutes a common gynecological disease among young women. The NLRP3 inflammasome may be activated and expressed in PD, but the mechanistic link between NLRP3 inflammasome activation and PD is still unclear. The assembly of the NLRP3 inflammasome as stimulated by NLRP3 irritants triggers proteolytic cleavage of dormant procaspase-1 into active caspase-1, which converts the cytokines pro-IL-1β and pro-IL-18 into mature and biologically active IL1β and IL-18, respectively, leading to a cascade of deleterious inflammation [10]. There is increasing evidence indicating that the NLRP3 inflammasome plays a regulatory role in the expression of COX-2 via the NF-κB pathway [11, 12]. We constructed a PD mouse model to investigate whether inhibition of NLRP3 inflammasomes through the NF-κB/COX-2/PG pathway exerts protective effects against PD induced by a combination of estradiol and oxytocin

Methods

Results

Discussion

Conclusion