Exposure to hyperandrogen drives ovarian dysfunction and fibrosis by activating the NLRP3 inflammasome in mice

Wang, Daojuan; Weng, Yajing; Zhang, Yaling; Wang, Rong; Wang, Tingyu; Zhou, Jianjun; Shen, Shanmei; Wang, Hongwei; Wang, Yong

doi:10.1016/j.scitotenv.2020.141049

Cited by 107 publications

(98 citation statements)

References 53 publications

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“…Studies have shown that NF-kB can inhibit the telomerase activity of GCs (42), thereby shortening the lifespan of GCs and preventing oocytes from sufficient nutrients. By producing NLRP3 inflammasomes, this inflammatory response promotes GC pyroptosis and ovarian fibrosis, and disrupts follicular formation (43). While the inflammatory factor IL-1 can inhibit FSHR and LHR, thereby inhibiting follicular maturation and inhibiting ovulation (15).…”

Section: Discussionmentioning

confidence: 99%

The Release of Peripheral Immune Inflammatory Cytokines Promote an Inflammatory Cascade in PCOS Patients via Altering the Follicular Microenvironment

Líu

Fan

et al. 2021

Front. Immunol.

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BackgroundHormones and immune imbalance are critical factors in polycystic ovary syndrome (PCOS). The alternation of immune microenvironment of oocytes may play a significant role in infertility of PCOS patients.ObjectiveThis study explores the role of follicular fluid microenvironment change in inflammatory pathways activation of granulosa cells (GCs) in PCOS women infertility.MethodsWe enrolled 27 PCOS patients and 30 controls aged 22 to 38 years who underwent IVF and collected their luteinized granulosa cells (LGCs). Meanwhile, a granulosa-like tumor cell line (KGN) as a cell-model assisted this study. Key inflammatory markers in human ovarian GCs and follicular fluid were detected by RT-qPCR, Western blotting, or ELISA. The KGN cells were treated with follicle supernatant mixed with normal medium to simulate the microenvironment of GCs in PCOS patients, and the inflammation indicators were observed. The assembly of NLRP3 inflammasomes was detected by immunofluorescence techniques. Dihydroethidium assay and EdU proliferation assay were used to detect ROS and cell proliferation by flow cytometry.ResultsCompared with normal controls (n = 19), IL-1β (P = 0.0005) and IL-18 (P = 0.021) in the follicular fluid of PCOS patients (n = 20) were significantly increased. The NF-κB pathway was activated, and NLRP3 inflammasome was formatted in ovarian GCs of PCOS patients. We also found that inflammation of KGN cells was activated with LPS irritation or stimulated by follicular fluid from PCOS patients. Finally, we found that intracellular inflammation process damaged mitochondrial structure and function, which induced oxidative stress, affected cellular metabolism, and impaired cell proliferation.ConclusionInflammatory microenvironment alteration in the follicular fluid of PCOS patients leads to activated inflammatory pathway in GCs, serving as a crucial factor that causes adverse symptoms in patients. This study provides a novel mechanism in the inflammatory process of PCOS.

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Section: Discussionmentioning

confidence: 99%

The Release of Peripheral Immune Inflammatory Cytokines Promote an Inflammatory Cascade in PCOS Patients via Altering the Follicular Microenvironment

Líu

Fan

et al. 2021

Front. Immunol.

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“…The LPS-induced inflammatory response occurs in multiple tissues including ovarian theca. As reported, the activation of TLR4/NF-κB signaling contributes to the ovulatory disruption by creating a pro-inflammatory environment in ovary (Wang et al, 2020a). Therefore, effective improve of the microbiota-driven inflammatory state could be a promising avenue to ameliorate PCOS.…”

Section: Introductionmentioning

confidence: 86%

“…Typically, females with PCOS are predisposed to have elevated levels of pro-inflammatory cytokines [e.g., interleukins (IL)-6 and IL-18] as well as the declined levels anti-inflammatory cytokines (e.g. IL-10 and IL-22) ( Qi et al, 2019 ; Wang et al, 2020a ). The imbalanced inflammatory state in PCOS ovaries could not only discount the insulin sensitivity but also impair the follicular growth.…”

Section: Introductionmentioning

confidence: 99%

Shaoyao-Gancao Decoction Ameliorates the Inflammation State in Polycystic Ovary Syndrome Rats via Remodeling Gut Microbiota and Suppressing the TLR4/NF-κB Pathway

et al. 2021

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Background: Emerging evidence suggests that gut microbiota plays a vital role in the occurrence of multiple endocrine disorders including polycystic ovary syndrome (PCOS). Shaoyao-Gancao Decoction (SGD), a classical Chinese prescription, has been widely used in the treatment of PCOS for decades. In previous studies, we found that SGD treatment could effectively reduce ovarian inflammation in PCOS rats. However, whether the anti-inflammation effect of SGD involves the regulation of the gut microbiota remains elusive.Methods: Letrozole-induced PCOS rat models were established, and the therapeutic effects of SGD were evaluated. Specifically, body weight, serum hormone concentrations, estrus phase and ovary histopathology were assessed. Then the structure of gut microbiota was determined by 16s rRNA sequencing. Additionally, the serum levels of pro-inflammatory cytokines and LPS were measured by ELISA kits. The key gene and protein expressions of TLR4/NF-κB signaling pathway were detected by quantitative real-time PCR and western blot.Results: SGD could effectively reduce body weight, regulate estrous cycles and ameliorate hyperandrogenism in PCOS rats. In addition, SGD treatment decreased releases of pro-inflammatory cytokines, enhanced the expressions of tight junction (occludin and claudin1), and then prevented a translocation of LPS into bloodstream. SGD could significantly reduce the ratio of Firmicutes to Bacteroidetes, decrease the abundance of LPS-producing pathogens Proteobateria and enrich the abundance of Butyricicoccus, Coprococcus, Akkermansia Blautia and Bacteroides in PCOS rats. Furthermore, SGD blunted the key gene and protein expressions of TLR4/NF-κB signaling pathway both in vivo and in LPS-induced RAW264.7 cells.Conclusion: SGD administration could ameliorate the inflammatory response in PCOS rats by remodeling gut microbiome structure, protecting gut barrier, and suppressing TLR4/NF-κB signaling pathway.

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“…The relationship between the NLRP3 in ammasome and brosis has been reported in various studies. The NLRP3 in ammasome can be activated by high androgen levels, leading to ovarian interstitial cell brosis [7] ; NLRP3 in ammasome activation is associated with the development of renal brosis in diabetic nephropathy [8] ; and NLRP3/IL-1β activation is associated with the formation of cardiac brosis [29] . However, the relationship between the NLRP3 in ammasome and liver brosis has rarely been reported.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies showed that NLRP3 in ammasome activation is associated with ovarian [7] , kidney [8] and heart [9] brosis. However, the role of the NOX4/NLRP3 signaling pathway in liver brosis has rarely been studied.…”

Section: Introductionmentioning

confidence: 99%

Ursolic acid reverses liver fibrosis by inhibiting NOX4/NLRP3 inflammasome pathways and bacterial dysbiosis

Liu

Nie

Zhang

et al. 2021

Preprint

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IntroductionActivation of the NOX4/NLRP3 inflammasome pathway has been associated with fibrosis in other organs. An imbalance in intestinal bacteria is an important driving factor of liver fibrosis through the liver-gut axis. This study aimed to explore whether the effect of ursolic acid (UA) on liver fibrosis was associated with the NOX4/NLRP3 inflammasome pathways and intestinal bacteriaMethodsWild-type (WT), NLRP3−/−, and NOX4−/− mice and AP-treated mice were injected with CCL4 and treated with or without UA.ResultUA alleviated liver fibrosis and the expression of NOX4 and NLRP3 was significantly inhibited by UA treatment. Even after CCL4 injection, liver damage and fibrosis-related factors were significantly decreased in NLRP3−/−, NOX4−/−, and AP-treated mice. Importantly, the expression of NLRP3 was obviously inhibited in NOX4−/− and AP-treated mice. In addition, the diversity of intestinal bacteria and the abundance of probiotics in NLRP3−/− and NOX4−/− mice was significantly higher than those in WT mice.ConclusionThe NOX4/NLRP3 inflammasome pathway plays a crucial role in liver fibrosis and is closely associated with the beneficial effect of UA. The mechanism by which the NOX4/NLRP3 pathway is involved in liver fibrosis may be associated with disordered intestinal bacteria.

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Exposure to hyperandrogen drives ovarian dysfunction and fibrosis by activating the NLRP3 inflammasome in mice

Cited by 107 publications

References 53 publications

The Release of Peripheral Immune Inflammatory Cytokines Promote an Inflammatory Cascade in PCOS Patients via Altering the Follicular Microenvironment

The Release of Peripheral Immune Inflammatory Cytokines Promote an Inflammatory Cascade in PCOS Patients via Altering the Follicular Microenvironment

Shaoyao-Gancao Decoction Ameliorates the Inflammation State in Polycystic Ovary Syndrome Rats via Remodeling Gut Microbiota and Suppressing the TLR4/NF-κB Pathway

Ursolic acid reverses liver fibrosis by inhibiting NOX4/NLRP3 inflammasome pathways and bacterial dysbiosis

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