High-mobility group box 1 (HMGB1) crosses the BBB bidirectionally.

Area of Science:

• Neuroscience
• Immunology
• Molecular Biology

Background:

• High-mobility group box 1 (HMGB1) is a nuclear protein and a damage-associated molecular pattern molecule.
• HMGB1 activates innate immunity via TLR4 and RAGE receptors, influencing cytokine-like signals that can cross the blood-brain barrier (BBB).
• Blood HMGB1 levels are elevated in various conditions, including stroke, sepsis, and senescence.

Purpose of the Study:

• To investigate the bidirectional transport of HMGB1 across the BBB.
• To determine the influence of inflammation on HMGB1's BBB transport.

Main Methods:

• Radioactive labeling of HMGB1 with iodine (I-HMGB1) for tracking.
• Measurement of unidirectional influx rate of I-HMGB1 into the mouse brain.
• Assessment of transport inhibition using unlabeled HMGB1 and receptor inhibitors (TLR4, TLR2, RAGE, CXCR4).
• Investigation of transport mechanisms, including absorptive transcytosis.
• Evaluation of I-HMGB1 transport in the context of lipopolysaccharide (LPS)-induced inflammation.

Main Results:

• I-HMGB1 demonstrated ready entry into the mouse brain with a unidirectional influx rate of 0.654 μl/g-min.
• All brain regions showed I-HMGB1 uptake, with the olfactory bulb having the highest and the striatum the lowest.
• Transport was not significantly inhibited by unlabeled HMGB1 or specific receptor inhibitors.
• Wheat germ agglutinin enhanced uptake, suggesting absorptive transcytosis.
• LPS-induced inflammation increased I-HMGB1 transport into the brain.
• I-HMGB1 was also transported from brain to blood, with HMGB1 and LPS enhancing this efflux.

Conclusions:

• HMGB1 can bidirectionally cross the BBB.
• Inflammation significantly enhances HMGB1 transport across the BBB in both directions.
• HMGB1's ability to cross the BBB and be modulated by inflammation provides a mechanism for its impact on neuroimmune signaling in both the brain and periphery.