Clinical chorioamnionitis is characterized by changes in the expression of the alarmin HMGB1 and one of its receptors, sRAGE

Abstract

Objective High-mobility group box-1 (HMGB1) protein is an alarmin, a normal cell constituent, which is released into the extracellular environment upon cellular stress/damage, and is capable of activating inflammation and tissue repair. The receptor for advanced glycation end products (RAGE) can bind HMGB1. RAGE, in turn, can induce the production of pro-inflammatory cytokines; this may be modulated the soluble truncated forms of RAGE, including soluble RAGE (sRAGE) and endogenous secretory RAGE (esRAGE). The objective of this study was to determine: 1) if clinical chorioamnionitis at term is associated with changes in amniotic fluid concentrations of HMGB1, sRAGE and esRAGE; and 2) if the amniotic fluid concentration of HMGB1 changes with labor or as a function of gestational age. Methods Amniotic fluid samples were collected from the following groups: 1) mid-trimester (MT) (n=45); 2) term with (n=48) and without labor (n=22) without intra-amniotic infection; and 3) term with clinical chorioamnionitis (n=46). Amniotic fluid concentrations of HMGB1, sRAGE and esRAGE concentrations were determined by ELISA. Results 1) the median amniotic fluid HMGB1 concentration was higher in patients at term with clinical chorioamnionitis than that of those without this condition (clinical chorioamnionitis: median 3.8 ng/mL vs. term in labor: median 1.8 ng/mL, p=0.007; and vs. term not in labor median 1.1 ng/mL, p=0.003); 2) in contrast, patients with clinical chorioamnionitis had a lower median sRAGE concentration than those without this condition (clinical chorioamnionitis: median 9.3 ng/mL vs. term in labor: median 18.6 ng/mL, p=0.001; and vs. term not in labor median 28.4 ng/mL, p<0.001); 3) amniotic fluid concentrations of esRAGE did not significantly change in patients with clinical chorioamnionitis at term (clinical chorioamnionitis: median 5.4 ng/mL vs. term in labor: median 6.1 ng/mL, p=0.9; and vs. term not in labor median 9.5 ng/mL, p=0.06); and 4) there was no significant difference in the median AF HMGB1 concentration between women at term in labor and those not in labor (p=0.4) and between women in the mid-trimester and those at term not in labor (mid-trimester: median 1.5 ng/mL; p=0.2). Conclusion An increase in the amniotic fluid HMGB1 concentration and a decrease in sRAGE were observed in clinical chorioamnionitis at term. This finding provides evidence that an alarmin, HMGB1, and one of its receptors, sRAGE, are engaged in the process of clinical chorioamnionitis at term. These changes are quite different from those observed in cases of intra-amniotic infection/inflammation in preterm gestations.

Sterile inflammation and pregnancy complications: a review

“…Interestingly, stimulation with endotoxins triggers HMGB1 expression and release in vitro in human fetal membranes (Bredeson et al 2014) and in vivo in murine fetuses when endotoxins are administered in dams (i.p.) (Buhimschi et al 2009); concordantly, women with intra-amniotic infection/ inflammation and women with chorioamnionitis have higher amniotic fluid levels of HMGB1 (Romero et al 2011, Romero et al 2012. The latter suggests that HMGB1 may also have an implication in the infectious etiology of preterm birth.…”

Damage-Associated Molecular Pattern and Fetal Membrane Vascular Injury and Collagen Disorganization in Lipopolysaccharide-Induced Intra-amniotic Inflammation in Fetal Sheep

“…Indeed, Romero et al found increased amniotic fluid levels of HMGB1 in women with preterm labor and/or PROM with intrauterine inflammation compared to those without intrauterine inflammation. 19,28 Furthermore, women without intrauterine inflammation but with PROM had a higher HMGB1 levels compared with women in preterm labor alone. In a recent study, Romero et al further demonstrated that women with sterile amniotic inflammation with higher HMGB1 levels have a decreased amniocentesis to delivery interval compared to women with lower amniotic fluid HMGB1 levels.…”

“…Changes in the expression of RAGE (receptor for HMGB1) have been implicated in sterile inflammation. 28 However, the mRNA expression and immunostaining of RAGE did not increase after exposure to IA LPS, which signals through Toll-like receptor 4 (TLR4; Figure 4A-C).…”

“…27 The amniotic fluid concentrations of other DAMPs, soluble RAGE, were increased in patients with clinical chorioamnionitis at term, and HSP70 concentrations were increased in patients with histological chorioamnionitis. 23,28 We use preterm sheep given IA injections of proinflammatory agonists to cause chorioamnionitis and multiple fetal organ injury responses similar to those reported in humans. 2,29 We hypothesized that IA injection of lipopolysaccharide (LPS) would increase DAMPs in the chorioamnion and compromise integrity of the fetal membranes.…”

Clinical chorioamnionitis at term: the amniotic fluid fatty acyl lipidome

“…We recently reported that TCC is a heterogeneous condition, as only 54% of patients have intra-amniotic infection (also called microbial-associated intra-amniotic inflammation), 24% have intra-amniotic inflammation without detectable microorganisms (sterile intra-amniotic inflammation), and 22% have no intra-amniotic inflammation (6). While the precise causes of sterile intra-amniotic inflammation are unknown, studies have shown that damage-associated molecular patterns, such as high mobility gene box-1, can elicit a sterile inflammatory response (17) and are elevated in the amniotic fluid of patients with TCC (18), and that this alarmin can induce labor (19). There is an urgent need for tests allowing the differential diagnosis of the three subgroups of patients with clinical chorioamnionitis, as these patients require different treatment.…”