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Enhancement of LPS-induced microglial inflammation response via TLR4 under high glucose conditions
Xiang Zhang1, Hongquan Dong, Susu Zhang
1Department of Anesthesiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Background:
Microglia activation mediated by toll-like receptor 4 (TLR4) plays an important role in neuroinflammation and postoperative cognitive dysfunction (POCD). Diabetes mellitus (DM) has been recently suggested as an independent risk factor for POCD. In this study, we investigate the potential exacerbation of the inflammatory response in primary microglia due to high glucose conditions.
Methods:
Primary microglial cells were exposed to normal glucose (25 mmol/L) and high glucose (35 mmol/L) levels alone or with lipopolyscaccharide (LPS 0, 2, 5, 10 ng/mL). The pro-inflammatory response of the cells was assessed by measuring changes in cytokine levels and the evaluation of associated signaling pathways.
Results:
Neither high glucose nor low LPS (≤5 ng/ml) alone had an effect on TNF-a and IL-6 levels, but the combination of low LPS and high glucose stimulated the inflammatory response. Analyses of the associated signaling pathways demonstrated that high glucose enhanced the LPS-induced microglial activation via the TLR4/JAK2/STAT3 pathway.
Conclusion:
This study demonstrates that high glucose, one of the key abnormalities characteristic of DM, can augment LPS-induced microglial activation and inflammatory cytokine levels through the TLR4/JAK2/STAT3 pathway, offering new insight into the pathophysiological relationship between DM and POCD.
Insights
High glucose exacerbates inflammation in microglia by enhancing toll-like receptor 4 (TLR4) activation, a key factor in neuroinflammation and postoperative cognitive dysfunction (POCD). This finding offers insight into diabetes mellitus (DM) and POCD links.
Area of Science:
- Neuroscience
- Immunology
- Endocrinology
Background:
- Microglia activation via toll-like receptor 4 (TLR4) is central to neuroinflammation and postoperative cognitive dysfunction (POCD).
- Diabetes mellitus (DM) is an emerging risk factor for POCD.
- This study examines how high glucose conditions impact microglial inflammatory responses.
Purpose of the Study:
- To investigate the role of high glucose in exacerbating microglial activation.
- To elucidate the signaling pathways involved in high glucose-induced microglial inflammation.
- To understand the link between diabetes mellitus and postoperative cognitive dysfunction.
Main Methods:
- Primary microglial cells were treated with normal (25 mmol/L) and high (35 mmol/L) glucose.
- Cells were co-exposed to varying concentrations of lipopolysaccharide (LPS).
- Pro-inflammatory cytokine levels (TNF-α, IL-6) and signaling pathways (TLR4/JAK2/STAT3) were analyzed.
Main Results:
- High glucose potentiated LPS-induced increases in TNF-α and IL-6 levels.
- High glucose enhanced LPS-induced microglial activation.
- The TLR4/JAK2/STAT3 pathway was identified as the mechanism mediating high glucose effects.
Conclusions:
- High glucose amplifies LPS-induced microglial activation and inflammatory cytokine release.
- The TLR4/JAK2/STAT3 pathway is crucial for this augmentation.
- Findings provide a molecular basis for the association between DM and POCD.
