Endogenous HMGB1 is required in endotoxin tolerance.

Area of Science:

• Immunology
• Molecular Biology
• Cellular Signaling

Background:

• High-mobility group box 1 protein (HMGB1) is a key inflammatory mediator in sepsis and endotoxemia.
• HMGB1 influences endotoxin tolerance by modulating cellular hyporesponsiveness and cytokine production (TNF-α, IL-1).

Purpose of the Study:

• To investigate the endogenous HMGB1 signaling pathways involved in low-dose lipopolysaccharide (LPS)-induced endotoxin tolerance.
• To understand HMGB1's role in cellular responses during the development of endotoxin tolerance.

Main Methods:

• Mice were preconditioned with low-dose LPS or PBS, followed by anti-HMGB1 antibody or control treatment.
• Mice were subsequently challenged with high-dose LPS, and serum and hepatic tissues were analyzed.
• Signaling mechanisms were further examined in cell cultures and tissues after HMGB1 or LPS preconditioning and high-dose LPS challenge.

Main Results:

• Low-dose LPS preconditioning necessitates increased endogenous HMGB1 expression and secretion.
• Anti-HMGB1 antibody treatment reversed endotoxin tolerance, increasing serum TNF-α and altering hepatic IL-1R-associated kinase M (IRAK-M) expression.
• Partial restoration of nuclear factor κB (NF-κB) activity was observed in vivo following HMGB1 neutralization.
• Translocation of HMGB1 from the nucleus to the cytoplasm occurred in RAW264.7 cells during LPS-induced tolerance.

Conclusions:

• Endotoxin tolerance induced by low-dose LPS involves increased endogenous HMGB1, leading to elevated IRAK-M and reduced NF-κB activity.
• These findings elucidate HMGB1's critical role in endotoxin tolerance, offering insights for developing targeted clinical therapeutics.