MiR-1224-5p attenuates polycystic ovary syndrome through inhibiting NOD-like receptor protein 3 inflammasome activation via targeting Forkhead box O 1

ABSTRACT

Polycystic ovary syndrome (PCOS) is a common endocrine disorder that poses a great threat to women's health. MiR-1224-5p is downregulated in the follicular fluid of patients with PCOS, but its role remains largely unknown. In this study, mice were treated with dehydroepiandrosterone (DHEA) to establish an in vivo model of PCOS. We found that enhanced activation of NLRP3 inflammasome was accompanied by downregulation of miR-1224-5p in ovarian tissue of PCOS mice. The effect of miR-1224-5p was further explored in TNF-α-treated human granulosa-like tumor (KGN) cells. Upregulation of miR-1224-5p suppressed TNF-α-induced secretion of DHEA and testosterone. MiR-1224-5p attenuated TNF-α-induced inflammation by inhibiting NLRP3 inflammasome activation, IL-1β synthesis, and nuclear factor kappa B (NF-κB) p65 nuclear translocation. Notably, miR-1224-5p decreased the expression of Forkhead box O 1 (FOXO1) and its downstream gene thioredoxin interaction protein (TXNIP). Luciferase reporter assay confirmed FOXO1 as a target of miR-1224-5p. Upregulation of FOXO1 abolished miR-1224-5p-induced activation of NLRP3 inflammasome, demonstrating that miR-1224-5p might inhibit NLRP3 inflammasome activation through regulating FOXO1. This study provided novel insights into the pathogenesis of PCOS and suggested that miR-1224-5p might be a promising target for treating PCOS.

KEYWORDS:

• Polycystic ovary syndrome
• miR-1224-5p
• human ovarian granulosa cells
• NLRP3 inflammasome
• FOXO1

Acknowledgements

This study was supported by a grant from the Discipline Boosting Program of The Fourth Military Medical University (No. XJZT18MJ26).

Highlights

• The expression of miR-1224-5p was decreased in DHEA-induced mouse model of PCOS.

• MiR-1224-5p inhibited NLRP3 inflammasome activation in TNF-α-induced KGN cells.

• MiR-1224-5p suppressed NF-κB signaling in TNF-α-induced KGN cells.

• MiR-1224-5p functioned through directly targeting FOXO1.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data of this study are available from the corresponding author upon reasonable request.

Ethical approval

The animal experiments were approved by the Ethics Committee of Xijing Hospital, Air Force Medical University [KY20193018].

Supplementary material

Supplemental data for this article can be accessed here

Additional information

Funding

This work was supported by the Discipline Boosting Program of the Fourth Military Medical University under Grant [No. XJZT18MJ26].