The Activation of CGAS-STING Pathway Causes Abnormal Uterine Receptivity in Aged Mice

Overview

Journal Aging Cell

Specialties Cell Biology
Geriatrics

Date 2024 Aug 8

PMID 39113346

Authors

Si-Ting Chen

Wen-Wen Shi

Feng Ran

Cheng-Kan Liu

Hui-Na Luo

Li-Juan Wu

Ying Wu

Tong-Tong Zhang

Zeng-Ming Yang

Affiliations

Soon will be listed here.

Abstract

Maternal age is one of the most important factors affecting the success of maternal pregnancy. Uterine aging is the leading cause of pregnancy failure in older women. However, how uterine aging affects uterine receptivity and decidualization is unclear. In this study, naturally aged one-year-old female mice were used to investigate effects of maternal age on embryo implantation during early pregnancy. In our study, we found abnormal uterine receptivity in aged mice. Aged mouse uterus indicates a decrease in nuclear LAMIN A, and an increase in PRELAMIN A and PROGERIN. In aged mouse uterus, double-stranded DNA (dsDNA) in cytoplasmic fraction is significantly increased. PROGERIN overexpression in mouse uterine epithelial cells and epithelial organoids leads to nuclear DNA leakage and impaired uterine receptivity. DNase I, DNase II, and TREX1 are obviously reduced in aged mouse uterus. Treatments with foreign DNA or STING agonist significantly downregulate uterine receptivity markers and activate cGAS-STING pathway. Uterine estrogen (E) concentration is significantly increased in aged mice. After ovariectomized mice are treated with a high level of E, there are significant increase of PROGERIN and cytoplasmic DNA, and activation of cGAS-STING pathway. CD14 is significantly increased in aged uterus. Intrauterine CD14 injection inhibits embryo implantation. In vitro CD14 treatment of cultured epithelial cells or epithelial organoids decreases uterine receptivity. Uterine abnormality in aged mouse can be partially rescued by STING inhibitor. In conclusion, uterine PROGERIN increase in aged mouse uterus results in cytoplasmic DNA accumulation and cGAS-STING pathway activation. CD14 secretion in aged uterus impairs uterine receptivity.

Citing Articles

The activation of cGAS-STING pathway causes abnormal uterine receptivity in aged mice.

Chen S, Shi W, Ran F, Liu C, Luo H, Wu L Aging Cell. 2024; 23(11):e14303.

PMID: 39113346 PMC: 11561655. DOI: 10.1111/acel.14303.

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