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Upregulation of HTRA1 mediated by the lncRNA NEAT1/miR-141-3p axis contributes to endometriosis development through activating NLRP3 inflammasome-mediated pyroptotic cell death and cellular inflammation

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Abstract

The present study identified a novel upstream long chain non-coding (lncRNA) NEAT1/miR-141-3p/HTRA1 axis that regulated the activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome to modulate endometriosis (EM) development. Specifically, clinical data suggested that the expression of NLRP3 and apoptosis-associated speck-like protein containing CARD (ASC), the cleavage of caspase-1 and gasdermin D (GSDMD), and the production of inflammatory cytokines (interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and IL-18) were all significantly increased in the ectopic endometrium (EE) tissues, compared to the normal endometrium (NE) tissues. Then, through analyzing the datasets from GEO database (GSE2339, GSE58178, and GSE7305) using the GEO2R bioinformatics tools, we verified that HtrA Serine Peptidase 1 (HTRA1) was especially enriched in the EE tissues compared to the NE tissues. To further confirm the biological functions of HTRA1, HTRA1 was overexpressed or downregulated in primary human endometrial stromal cells (hESCs) isolated from NE tissues or EE tissues, respectively. The results showed that upregulation of HTRA1 activated NLRP3 inflammasome-mediated pyroptotic cell death and cellular inflammation in NE-derived hESCs, whereas silencing of HTRA1 played an opposite role in EE-derived hESCs. In addition, the lncRNA NEAT1/miR-141-3p axis was screened as the upstream regulator of HTRA1. Mechanistically, lncRNA NEAT1 sponged miR-141-3p to positively regulate HTRA1 in a competing endogenous RNA (ceRNA) mechanisms-dependent manner. The recovery experiments in hESCs from NE and EE tissues confirmed that lncRNA NEAT1 overexpression promoted NLRP3 inflammasome-mediated pyroptotic cell death through regulating the miR-141-3p/HTRA1 axis. Taken together, this study firstly uncovered the underlying mechanisms by which a novel lncRNA NEAT1/miR-141-3p/HTRA1-NLRP3 pathway contributed to the development of EM, which provided novel diagnostic and therapeutic biomarkers for this disease.

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The data were all included in this manuscript. The original data are available from the corresponding author upon reasonable request.

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Acknowledgements

Not applicable.

Funding

The research was funded by Yunnan Provincial Clinical Research Center for Obstetrics and Gynecology (Project No.2022YJZX-FC07), the Doctor Research Fund of The First People’s Hospital of Yunnan Province (KHBS-2020-003) and the Yunnan Provincial Department of Science and Technology-Kunming Medical University Joint Special Project on Applied Basic Research (202201AY070001-229).

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  1. Lingchuan Li and Kefan Ye contributed equally.

Authors and Affiliations

  1. Department of Gynaecology, The First People’s Hospital of Yunnan Province, Kunming, 650032, Yunnan, China

    Lingchuan Li, Kefan Ye & Dongjie Wang

  2. The Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650032, Yunnan, China

    Lingchuan Li, Kefan Ye & Dongjie Wang

  3. Department of Gynaecology, The Affiliated Hospital of Kunming University of Science and Technology, 157 Jinbi Road, Kunming, 650032, Yunnan, China

    Dongjie Wang

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11626_2023_760_MOESM1_ESM.jpg

Supplementary file1 Venn diagram of overlapping down-regulated genes from 3 GSE dataset of EM (GSE23339, GSE58178 and GSE7305). (JPG 769 KB)

11626_2023_760_MOESM2_ESM.jpg

Supplementary file2 (A) Cell morphology of NE-derived hESCs transfected with pcDNA-NEAT1, miR-141-3p mimic or siRNA- HTRA1 was observed under a microscope (scale bar = 100µm). (B) Cell morphology of EE-derived hESCs transfected with siRNA-NEAT1, miR-141-3p inhibitor or pcDNA- HTRA1 (scale bar = 100µm). (C) Cell viability of NE-derived hESCs transfected with pcDNA-NEAT1, miR-141-3p mimic or siRNA- HTRA1 was determined by cell counting Kit-8 (CCK-8) assay. (C) Cell viability of EE-derived hESCs transfected with siRNA-NEAT1, miR-141-3p inhibitor or pcDNA- HTRA1. (nsP＞0.05 , *P＜0.05). (JPG 2962 KB)

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Supplementary file4 (DOCX 16 KB)

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Li, L., Ye, K. & Wang, D. Upregulation of HTRA1 mediated by the lncRNA NEAT1/miR-141-3p axis contributes to endometriosis development through activating NLRP3 inflammasome-mediated pyroptotic cell death and cellular inflammation. In Vitro Cell.Dev.Biol.-Animal 59, 166–178 (2023). https://doi.org/10.1007/s11626-023-00760-8

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