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Comment |
Exposure to hyperandrogen drives ovarian dysfunction and fibrosis by activating the NLRP3 inflammasome in mice. Wang D et al. (2020) Hyperandrogenism is the main cause of infertility as a result of polycystic ovary syndrome (PCOS). Long-term and continuous exposure to hyperandrogen can cause follicular developmental disorders. Ovarian granulosa cells (GCs) are critical in shaping the follicular development. To clarify how excessive androgen suppresses folliculogenesis and ovulation, we constructed PCOS mice by implantation of a 35-d testosterone (T) continuous-release pellet. Ovarian toll-like receptor 4 (TLR4) expression and serum IL-6 and IL-1β levels were dramatically increased in T-treated mice. In addition, the expression of NLRP3 inflammasome in the ovary of T-treated mice suggests that pyroptosis may play an essential role in follicular dysfunction. Lipopolysaccharide (LPS) has been extensively studied for activating cells by binding to TLR4. In this study, we demonstrated that LPS-induced inflammation leads to activation of the NLRP3 inflammasome with consequent impacts on follicular dysfunction. Herein we showed that LPS treatment upregulated the expression of 3β-hydroxysteroid dehydrogenase (3β-HSD) and androgen receptor (AR), while suppressed follicle stimulating hormone receptor (FSHR) expression in vitro. Moreover, we overexpressed NLRP3 using nigericin or lentiviral particles in GCs. The protein and mRNA levels of pyroptotic factors were highly enhanced with NLRP3 overexpression. As expected, the expression of Cyp19α1, Cyp11α1, 3β-HSD and FSHR at both the protein and mRNA levels was also markedly increased with excessive NLRP3. After inhibiting NLRP3, dihydrotestosterone (DHT)-treated GCs demonstrated markedly decreased NLRP3, the inflammasome adapter protein ASC, C-terminal fragment of gasdermin D (GSDMD-C), AR and Cyp19α1 at the protein level. Furthermore, with NLRP3 overexpression, the expression of fibrotic factors in ovarian cells was dramatically increased, such as TGF-β, CTGF, α-SMA, β-catenin, collagen I and collagen IV. These findings suggest that hyperandrogen stimulates chronic low-grade inflammation in the ovary to activate the NLRP3 inflammasome, further inducing a series of pathologies including ovarian GC pyroptotic death, follicular dysfunction and ovarian interstitial cell fibrosis.//////////////////Expression and Contribution of NLRP3 Inflammasome During the Follicular Development Induced by PMSG. Zhang Z et al. (2019) Follicular development and following ovulation induced by luteinizing hormone (LH) surge are critical for ovarian functions, but the molecular mechanism regulating ovarian ovulation attracts more attention and remains mainly unknown. Recent researches on the nucleotide leukin rich polypeptide 3 (NLRP3) inflammasome shred light on it. Given pregnant mare serum gonadotropin (PMSG) can not only trigger the follicular development, but also induce the following ovulation, the present study therefore examined that expression and localization of NLRP3 inflammasome through immunohistochemistry and Western blotting during the follicular development induced by PMSG. The results showed expressions of NLRP3 and the adaptor protein apoptosis-associated speck-like protein (ASC) significantly increased in the outside of intrafollicular fluid, further analysis found that caspase-1 was activated and IL-1β production was also upregulated after 52 h-treatment of PMSG. Furthermore, a significant increase of ovulation-related genes, hypoxia inducible factor (HIF)-1α and endothelin (ET)-1, was found after 52 h-treatment of PMSG. To our knowledge, it is the first time to clearly indicated the activation of NLRP3 inflammasome may contribute to the ovulation of PMSG-treated ovaries, which will help to further clarify the ovulatory mechanism in mammals.//////////////////.https://www.sciencedirect.com/science/article/pii/S0161589020304879
N-acetylcysteine modulates non-esterified fatty acid-induced pyroptosis and inflammation in granulosa cells
...Wang et al 2020 In the perinatal period of dairy cows, negative energy balance (NEB) is likely to occur, which increases the level of non-esterified fatty acids (NEFA) in the follicular fluid, hinders the proliferation of granulosa cells (GCs), and thus endangers the development of oocytes and the fecundity of dairy cows. We found that there were oxidative stress and inflammatory response in the serum of cows with perinatal ketosis. Whether the oxidative stress induced by NEFA is involved in the pyroptosis and inflammation of GCs remains unclear. After NEFA treatment, the expression of NLRP3 and caspase-1 and the release of inflammatory cytokines IL-1β were increased in a dose-dependent manner, indicating that NEFA may contribute to pyroptosis. Besides, NEFA stimulation induced oxidative stress, resulting in the phosphorylation of NF-κB, and increased the production of interleukin (IL)-6 and nitric oxide (NO), indicating that NEFA may induce inflammation in GCs. However, the NEFA-mediated effects were observably reversed when the GCs were pre-treated with antioxidant and radical scavenger, N-acetylcysteine (NAC). Taken together, our results reveal that NEFA can induce pyroptosis and inflammation through NLRP3 inflammasome and TLR4/NF-κB pathway, respectively, and NAC can alleviate these conditions.
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Comment |
Polystyrene microplastics lead to pyroptosis and apoptosis of ovarian granulosa cells via NLRP3/Caspase-1 signaling pathway in rats. Hou J et al. (2021) Microplastics (MPs) considered as a new persistent environmental pollutant could enter into the circulatory system and result in decrease of sperm quantity and quality in mice. However, the effects of Polystyrene MPs (PS MPs) on the ovary and its mechanism in rats remained unclear. In this present study, thirty-two healthy female Wistar rats were exposed to different concentrations of 0.5 µm PS MPs dispersed in deionized water for 90 days. Using hematoxylin-eosin (HE) staining, the number of growing follicles was decreased compared to the control group. In addition, the activity of glutathione peroxidase (GSH-Px), catalase (CAT) and superoxide dismutase (SOD) were decreased while the expression level of malondialdehyde (MDA) was increased in ovary tissue. Confirmed by immunohistochemistry, the integrated optical density of NLRP3 and Cleaved-Caspase-1 had been elevated by 13.9 and 14 in granulosa cells in the 1.5 mg/kg/d group. Furthermore, compared to the control group, the level of AMH had been decreased by 23.3 pg/ml while IL-1β and IL-18 had been increased by 32 and 18.5 pg/ml in the 1.5 mg/kg/d group using the enzyme-linked immune sorbent assay (ELISA). Besides, the apoptosis of granulosa cells was elevated measured by terminal deoxyribonucleotide transferase-mediated nick end labeling (TUNEL) staining and flow cytometry. Moreover, western blot assays showed that the expressions of NLRP3/Caspase-1 signaling pathway related factors and Cleaved-Caspase-3 were increased. These results demonstrated that PS MPs could induce pyroptosis and apoptosis of ovarian granulosa cells via the NLRP3/Caspase-1 signaling pathway maybe triggered by oxidative stress. The present study suggested that exposure to microplastics had adverse effects on ovary and could be a potential risk factor for female infertility, which provided new insights into the toxicity of MPs on female reproduction.//////////////////
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Mutations |
2 mutations
Species: mouse
Mutation name:
type: null mutation
fertility: fertile
Comment: Inhibition of the NLRP3 inflammasome prevents ovarian aging. Navarro-Pando JM et al. (2021) Inflammation is a hallmark of aging and is negatively affecting female fertility. In this study, we evaluate the role of the NLRP3 inflammasome in ovarian aging and female fertility. Age-dependent increased expression of NLRP3 in the ovary was observed in WT mice during reproductive aging. High expression of NLRP3, caspase-1, and IL-1β was also observed in granulosa cells from patients with ovarian insufficiency. Ablation of NLRP3 improved the survival and pregnancy rates and increased anti-Müllerian hormone levels and autophagy rates in ovaries. Deficiency of NLRP3 also reduced serum FSH and estradiol levels. Consistent with these results, pharmacological inhibition of NLRP3 using a direct NLRP3 inhibitor, MCC950, improved fertility in female mice to levels comparable to those of Nlrp3-/- mice. These results suggest that the NLRP3 inflammasome is implicated in the age-dependent loss of female fertility and position this inflammasome as a potential new therapeutic target for the treatment of infertility.//////////////////
Species: mouse
Mutation name:
type: null mutation
fertility: fertile
Comment: The Inflammasome Contributes to Depletion of the Ovarian Reserve During Aging in Mice. Lliberos C et al. (2021) Ovarian aging is a natural process characterized by follicular depletion and a reduction in oocyte quality, resulting in loss of ovarian function, cycle irregularity and eventually infertility and menopause. The factors that contribute to ovarian aging have not been fully characterized. Activation of the NLRP3 inflammasome has been implicated in age-associated inflammation and diminished function in several organs. In this study, we used Asc-/- and Nlrp3-/- mice to investigate the possibility that chronic low-grade systemic inflammation mediated by the inflammasome contributes to diminished ovarian reserves as females age. Pro-inflammatory cytokines, IL-6, IL-18, and TNF-α, were decreased in the serum of aging Asc-/- mice compared to WT. Within the ovary of reproductively aged Asc-/- mice, mRNA levels of major pro-inflammatory genes Tnfa, Il1a, and Il1b were decreased, and macrophage infiltration was reduced compared to age-matched WT controls. Notably, suppression of the inflammatory phenotype in Asc-/- mice was associated with retention of follicular reserves during reproductive aging. Similarly, the expression of intra-ovarian pro-inflammatory cytokines was reduced, and follicle numbers were significantly elevated, in aging Nlrp3-/- mice compared to WT controls. These data suggest that inflammasome-dependent inflammation contributes to the age-associated depletion of follicles and raises the possibility that ovarian aging could be delayed, and fertile window prolonged, by suppressing inflammatory processes in the ovary.//////////////////
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