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NLRP3 Inflammasome-dependent Pathway is Involved in the Pathogenesis of Polycystic Ovary Syndrome

  • Reproductive Biology: Original Article
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Abstract

Accumulating evidence has shown that inflammation is a key process in polycystic ovary syndrome (PCOS). Nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing 3 (NLRP3) inflammasomes play an essential role in inflammation. We investigated the expression of NLRP3 inflammasome in PCOS and its underlying mechanisms. Human granulosa cells (GCs) were isolated from patients with PCOS and control women who underwent in vitro fertilization and embryo transfer. Ovarian specimens were collected from mice with polycystic ovarian changes induced by a high-fat diet and letrozole. RNA sequencing (RNA-Seq) was performed on a granulosa cell line (KGN) overexpressing NLRP3. Polymerase chain reaction (PCR) was performed to quantify the differentially expressed genes of interest. NLRP3 and caspase-1 expression was significantly higher in GCs from patients with PCOS than in GCs from the control group. Increased NLRP3 and caspase-1 expression was also detected by immunohistochemistry in the GCs of a mouse model of polycystic ovarian changes. The serum IL-18 concentration in PCOS-like mice was significantly higher than that in control mice. Following NLRP3 overexpression in KGN cells, the genes involved in N-glycan processing, steroidogenesis, oocyte maturation, autophagy, and apoptosis were upregulated. The RT-qPCR results revealed that the expression levels of GANAB, ALG-5, HSD3B2, ULK1, PTK2B, and Casp7 in KGN cells after NLRP3 overexpression were significantly higher than those in control cells, which was consistent with the RNA-Seq results. Taken together, the NLRP3 inflammasome-dependent pathway is involved in the pathogenesis of PCOS not only by mediating pyroptosis, but also by regulating glycan synthesis, sex hormone synthesis, autophagy, and apoptosis in GCs.

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Data availability

All data obtained or analyzed in this study are included in this article and are available from the corresponding authors.

Abbreviations

NLRP3:

Nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3

PCOS:

Polycystic ovary syndrome

DEGs:

Differentially expressed genes

GO:

Gene Ontology

RNA-Seq:

RNA sequencing

qRT PCR:

Quantitative RT-PCR

KEGG:

Kyoto Encyclopedia of Genes and Genome

GANAB:

Glucosidase II Alpha Subunit

ALG5:

Asparagine-Linked Glycosylation 5

HSD3B2:

Hydroxy-Delta-5-Steroid Dehydrogenase, 3 Beta- And Steroid Delta-Isomerase 2

ULK1:

Unc-51 Like Autophagy Activating Kinase 1

PTK2B:

Protein Tyrosine Kinase 2 Beta

CASP7:

Caspase-7

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Acknowledgements

The authors are grateful to Prof. Hongli Yan and the medical staff of Shanghai Changhai Hospital for helping with the case samples collection and information.

Funding

This work was supported by the Programs Foundation of Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, under Grant (No. YJ-12, 2016–2018, Bo Wang). Shanghai Key Laboratory of Embryo Original Diseases (Shelab201902, Bo Wang, Guolian Ding).

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Authors and Affiliations

  1. Department of Reproductive Medicine, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200092, China

    Bo Wang, Yi Zhang, Bin Liu & Di Xi

  2. Shanghai Changhai Hospital, Shanghai, 200433, China

    Minfeng Shi

  3. Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, 200011, China

    Chuanjin Yu, Hefeng Huang & Guolian Ding

  4. School of Medicine, International Peace Maternity and Child Health Hospital, Shanghai Jiaotong University, Shanghai, 200030, China

    Hong Pan & Haiqing Shen

  5. Ministry of Education-Shanghai Key Laboratory of Children’s Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China

    Yatao Du

  6. Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China

    Hefeng Huang & Guolian Ding

  7. Key Laboratory of Reproductive Genetics (Ministry of Education), Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China

    Jianzhong Sheng & Hefeng Huang

  8. School of Medicine, The Fourth Affiliated Hospital of Zhejiang University, Yiwu, 322000, China

    Jianzhong Sheng

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  1. Bo Wang
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Contributions

WB, DGL, and HHF contributed to study design, data acquisition and interpretation, and manuscript drafting. WB, SMF, YCJ, PH, SHQ, BL, and XD collected samples and contributed to data analysis and interpretation. DGL, YCJ, DYT, and SJZ critically revised the manuscript. All the authors have read and approved the final version of the manuscript.

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Correspondence to Bo Wang, Hefeng Huang or Guolian Ding.

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Wang, B., Shi, M., Yu, C. et al. NLRP3 Inflammasome-dependent Pathway is Involved in the Pathogenesis of Polycystic Ovary Syndrome. Reprod. Sci. 31, 1017–1027 (2024). https://doi.org/10.1007/s43032-023-01348-z

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