Characterization of RAGE, HMGB1, and S100β in Inflammation-Induced Preterm Birth and Fetal Tissue Injury

Abstract

Immune activation represents an adaptive reaction triggered by both noxious exogenous (microbes) and endogenous [high mobility group box-1 protein (HMGB1), S100 calcium binding proteins] inducers of inflammation. Cell stress or necrosis lead the release of HMGB1 and S100 proteins in the extracellular compartment where they act as damage-associated molecular pattern molecules (or alarmins) by engaging the receptor for advanced glycation end-products (RAGE). Although the biology of RAGE is dictated by the accumulation of damage-associated molecular pattern molecules at sites of tissue injury, the role of RAGE in mediating antenatal fetal injury remains unknown. First, we studied the relationships at birth between the intensity of human fetal inflammation and sRAGE (an endogenous RAGE antagonist), HMGB1, and S100␤ protein. We found significantly lower sRAGE in human fetuses that mounted robust inflammatory responses. HMGB1 levels correlated significantly with levels of interleukin-6 and S100␤ in fetal circulation. We then evaluated the levels and areas of tissue expression of RAGE, HMGB1, and S100␤ in specific organs of mouse fetuses on E16. Using an animal model of endotoxin-induced fetal damage and preterm birth, we determined that inflammation induces a significant change in expression of RAGE and HMGB1, but not S100␤, at sites of tissue damage. Our findings indicate that RAGE and Conventional wisdom holds that the primary causes of the high neonatal morbidity and mortality attendant preterm birth are complications of immature organ systems.1-4 However, a growing body of investigation suggests that the poor outcome observed in many preterm children is not entirely dependent on their gestational age at birth. 2,5,6 After correcting for gestational age, several risk factors remain significantly associated with an increased risk of cerebral palsy, such as intra-amniotic infection, histological chorioamnionitis, prolonged rupture of the membranes, and hypoxemic fetal growth re-

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.…”

High Mobility Group-Box 1 (HMGB1) levels are increased in amniotic fluid of women with intra-amniotic inflammation-determined preterm birth, and the source may be the damaged fetal membranes

“…7 Furthermore, our group demonstrated for the first time that components of the Damage Associated Molecular Pattern & Receptor for Advance Glycation End Product (DAMP-RAGE) system, in particular the alarmin S100A12 (EN-RAGE) and the RAGE antagonist soluble RAGE (sRAGE), are present in human amniotic fluid (AF). In women with intra-amniotic infection, levels of S100A12 were found to be determined by the severity of intra-amniotic inflammation (IAI).…”

High-mobility group box-1 protein in tracheal aspirates from premature infants: relationship with bronchopulmonary dysplasia and steroid therapy

“…1 A recent report has implicated HMGB1 in an animal model of chorioamnionitis. 19 Interestingly, both TNF-a and IL-1b, known to be early-release cytokines in response to injurious stimuli and potent inducers of the late-release cytokine HMGB1, have been implicated in animal models 20,21 and human 22 BPD. Although we were unable to locate any reports of HMGB1 in developmentally appropriate animal models of BPD, HMGB1 has been reported to mediate the inflammatory cascade in an experimental model of necrotizing enterocolitis in neonatal rats.…”