Regulatory mechanisms of HMGB1 and its receptors in polycystic ovary syndrome-driven gravid uterine inflammation. : Gravid uterine HMGB1 and TLR2/4 in PCOS

• High-mobility group box 1 (HMGB1) is critical for inflammatory homeostasis and successful pregnancy, and there is a strong association between elevated levels of HMGB1, polycystic ovary syndrome (PCOS), chronic inflammation, and pregnancy loss. However, the mechanisms responsible for PCOS-driven regulation of uterine HMGB1 and its candidate receptors (toll-like receptor (TLR) 2 and 4) and inflammatory responses during pregnancy remain unclear. In this study, we found a gestational stage-dependent 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-related signaling pathways in the gravid uterus exposed to 5α-dihydrotestosterone 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-related 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-like rat uterus, PCOS endometrium, and pregnant rat uterus with hemorrhagic and resorbed fetuses, possibly via activation of nuclear factor κB signaling. These results suggest that both AR-dependent and AR-independent mechanisms contribute to the modulation of HMGB1/TLR2/TLR4-mediated uterine inflammation. We propose that elevation of HMGB1 and its receptors and disruption of the pro-/anti-inflammatory balance in the gravid uterus may participate in the pathophysiology of PCOS-associated pregnancy loss.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Hälsovetenskap (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Health Sciences (hsv//eng)

Nyckelord

HMGB1

toll-like receptors

androgen receptor

lipopolysaccharide

gravid uterus

polycystic ovary syndrome

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)