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However, the mechanisms responsible for PCOS\u2010driven regulation of uterine HMGB1 and its candidate receptors [toll\u2010like receptor (TLR) 2 and 4] and inflammatory responses during pregnancy remain unclear. In this study, we found a gestational stage\u2010dependent decrease in uterine HMGB1 and TLR4 protein abundance in rats during normal pregnancy. We demonstrated that increased expression of HMGB1, TLR2 and TLR4 proteins was associated with activation of inflammation\u2010related signalling pathways in the gravid uterus exposed to 5\u03b1\u2010dihydrotestosterone and insulin, mimicking the clinical features (hyperandrogenism and insulin resistance) of PCOS and this elevation was completely inhibited by treatment with the androgen receptor (AR) antagonist flutamide. Interestingly, acute exposure to lipopolysaccharide suppressed HMGB1, TLR4 and inflammation\u2010related protein abundance but did not affect androgen levels or AR expression in the gravid uterus with viable fetuses. Furthermore, immunohistochemical analysis revealed that, in addition to being localized predominately in the nuclear compartment, HMGB1 immunoreactivity was also detected in the cytoplasm in the PCOS\u2010like rat uterus, PCOS endometrium and pregnant rat uterus with haemorrhagic and resorbed fetuses, possibly via activation of nuclear factor \u03baB signalling. These results suggest that both AR\u2010dependent and AR\u2010independent mechanisms contribute to the modulation of HMGB1\/TLR2\/TLR4\u2010mediated uterine inflammation. We propose that the elevation of HMGB1 and its receptors and disruption of the pro\u2010\/anti\u2010inflammatory balance in the gravid uterus may participate in the pathophysiology of PCOS\u2010associated pregnancy loss.<\/jats:p>","DOI":"10.1111\/febs.16678","type":"journal-article","created":{"date-parts":[[2022,11,16]],"date-time":"2022-11-16T07:15:51Z","timestamp":1668582951000},"page":"1874-1906","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Regulatory mechanisms of <scp>HMGB1<\/scp> and its receptors in polycystic ovary syndrome\u2010driven gravid uterine inflammation"],"prefix":"10.1111","volume":"290","author":[{"given":"Min","family":"Hu","sequence":"first","affiliation":[{"name":"Department of Traditional Chinese Medicine The First Affiliated Hospital of Guangzhou Medical University  China"},{"name":"Institute of Integrated Traditional Chinese Medicine and Western Medicine Guangzhou Medical University  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