Excess glucose induce trophoblast inflammation and limit cell migration through HMGB1 activation of Toll-Like receptor 4

Am J Reprod Immunol. 2018 Nov;80(5):e13044. doi: 10.1111/aji.13044. Epub 2018 Sep 2.


Problem: Hyperglycemia increases the risk of preeclampsia. Hyperglycemia induces a placental trophoblast inflammatory (IL-1β, IL-6, IL-8), antiangiogenic (sFlt-1, sEndoglin), and anti-migratory profile. The IL-1β response is mediated via inflammasome activation by the damage-associated molecular pattern (DAMP), uric acid. The objective of this study was to determine the role of high-mobility group box-1 (HMGB1), a DAMP that activates Toll-like receptor 4 (TLR4), in human first trimester trophoblast responses to hyperglycemia. The trophoblast response to excess glucose under different oxygen tensions was also investigated.

Method of study: The human first trimester trophoblast cell line (Sw.71) was exposed to glucose mimicking normoglycemia (5 mmol/L) and hyperglycemia (10 mmol/L), either alone or with the TLR4 antagonist, LPS-RS; or the HMGB1 inhibitor, glycyrrhizin. Cells were also treated with glucose under hyperoxic (21% O2 ), normoxic (8% O2 ), and hypoxic (2% O2 ) conditions. Cell-free supernatants were assayed by ELISA and bioassays for inflammatory: IL-1β, IL-6, and IL-8; inflammasome-associated: uric acid and caspase-1; angiogenic: sEndoglin, sFlt-1, and PlGF; and the DAMP, HMGB1. Cell migration was measured using a two-chamber colormetric assay.

Results: Excess glucose triggered a trophoblast sterile inflammatory IL-8 and antimigratory response through HMGB1 activation of TLR4. The IL-1β and sFlt-1/PlGF response was TLR4-mediated, but HMGB1-independent, suggesting another DAMP may be involved. Hyperoxia rather than normoxia or hypoxia was a major driver of trophoblast dysfunction in response to excess glucose.

Conclusion: The findings from this study indicate a novel mechanism by which hyperglycemia may impact trophoblast function, early placentation, and ultimately, pregnancy outcome.

Keywords: diabetes; immunology; placenta; preeclampsia; pregnancy; trophoblast.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alarmins / metabolism*
  • Cell Line
  • Cell Movement
  • Female
  • Glycyrrhizic Acid / pharmacology
  • HMGB1 Protein / antagonists & inhibitors
  • HMGB1 Protein / metabolism*
  • Humans
  • Hyperglycemia / immunology*
  • Inflammation / immunology*
  • Interleukin-1beta / metabolism
  • Interleukin-8 / metabolism
  • Pre-Eclampsia / immunology*
  • Pregnancy
  • Risk
  • Signal Transduction
  • Toll-Like Receptor 4 / metabolism*
  • Trophoblasts / immunology*
  • Trophoblasts / pathology
  • Vascular Endothelial Growth Factor Receptor-1 / metabolism


  • Alarmins
  • HMGB1 Protein
  • Interleukin-1beta
  • Interleukin-8
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • Glycyrrhizic Acid
  • FLT1 protein, human
  • Vascular Endothelial Growth Factor Receptor-1