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Hyperglycemia-induced placental inflammation involves differential activation of RAGE-associated PI3K/MAPK/NF-κB signaling pathways
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DOI：10.1186/s10020-026-01604-3.png)
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Abstract
En 中文
Exposure to elevated glucose levels during intrauterine life is detrimental to both the mother and fetus. As a glucose-sensitive organ, the placenta responds to hyperglycemia by mounting a pro-inflammatory response characterized by increased production of inflammatory mediators that disrupt the immune privilege of the maternal-fetal interface. Although hyperglycemia promotes inflammation in human placental tissue, the molecular mechanisms through which HMGB1 release and advanced glycation end products (AGEs) accumulation converge on RAGE-associated signaling pathways to sustain this response remain poorly understood. To investigate the molecular mechanisms by which hyperglycemia activates HMGB1/AGEs-dependent signaling networks leading to inflammatory responses in human placental villi. Human term placental villous explants were exposed to normal or high glucose concentrations for 1–9 h or 48 h. For pathway inhibition experiments, explants were treated with selective inhibitors during high-glucose exposure. Inflammatory mediators, extracellular HMGB1, glyoxal-derived AGEs, TLR4 and RAGE expression, and activation of Akt1, ERK1/2, and NF-κB were evaluated. High-glucose exposure elicited a pro-inflammatory phenotype characterized by increased extracellular HMGB1 release, enhanced glyoxal-derived AGEs formation, and elevated TLR4 expression, supporting the involvement of HMGB1/AGE-RAGE signaling. Mechanistically, hyperglycemia was associated with activation of the PI3K/Akt and MAPK/ERK1/2 pathways, promoting NF-κB activation, suggesting the participation of both RAGE-dependent and RAGE-independent mechanisms, leading to increased secretion of TNF-α, IL-1β, and IL-6. Pharmacological inhibition experiments suggested the existence of putative interconnected positive feedback loops linking AGE accumulation, HMGB1 release, RAGE activation, and downstream inflammatory signaling, supporting the establishment of a self-sustaining metainflammatory network in placental villi. Collectively, these findings provide insight into the mechanisms by which sustained maternal hyperglycemia reshapes placental immune signaling and promotes a chronic metainflammatory state that may compromise placental function. Our results support a mechanistic model in which HMGB1/AGE-RAGE/TLR4 signaling contributes to placental dysfunction during gestational hyperglycemia.
Keywords:
Gestational diabetes mellitus
Placental inflammation
Metainflammation
Hyperglycemia
HMGB1
Advanced glycation end products (AGEs)
RAGE signaling
TLR4
NF-κB
Placental villous explants
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