To synthesize current understanding of the reciprocal interactions between lipopolysaccharide (LPS) and high mobility group box 1 protein (HMGB1) in sepsis and explore emerging therapeutic opportunities.
Approach:
Mechanistic Overview: The review defines the LPS-HMGB1-caspase-11/4/5 axis as a mechanism of inflammatory amplification in sepsis, detailing the interactions and pathways involved, including the internalization of LPS through HMGB1.
Key Findings:
LPS initiates inflammatory and coagulation cascades through TLR4 and cytosolic caspases (caspase-11 in mice, caspases-4 and -5 in humans).
HMGB1 forms complexes with LPS, which are internalized and lead to caspase activation and inflammatory amplification.
Caspase-11 activation is a significant driver of severe sepsis and septic shock, as evidenced by murine models.
The role of HMGB1 in the internalization of LPS and its impact on caspase activation is critical.
Interpretation:
The findings suggest that the LPS-HMGB1-caspase axis is crucial for understanding sepsis pathophysiology, although the translation of these findings to human clinical sepsis is still under investigation.
Limitations:
Most mechanistic insights are derived from murine models, which may not fully represent human sepsis.
The contributions of TLR4 and cytosolic pathways in human sepsis need further investigation.
Conclusion:
The review highlights the importance of the LPS-HMGB1 interaction in sepsis and suggests potential therapeutic avenues targeting HMGB1, though clinical applications have not yet been realized.
