The HMGB1 receptor RAGE mediates ischemic brain damage.

Area of Science:

• Neuroscience
• Immunology
• Molecular Biology

Background:

• Ischemic stroke involves a necrotic core surrounded by inflammation, leading to delayed cell death and worsened brain damage.
• The receptor for advanced glycation end products (RAGE) and its ligand high mobility group box 1 (HMGB1) are implicated in inflammatory processes.

Purpose of the Study:

• To investigate the role of the HMGB1-RAGE axis in sensing necrotic cell death and mediating inflammation and brain damage in ischemic stroke.
• To explore HMGB1-RAGE signaling as a potential therapeutic target for stroke.

Main Methods:

• Measuring HMGB1 levels in stroke patients' serum and in a mouse model of cerebral ischemia.
• Administering anti-HMGB1 antibodies and HMGB1 antagonists (HMGB1 box A) in mouse stroke models.
• Utilizing RAGE-deficient mice and soluble RAGE (decoy receptor).
• Investigating RAGE expression in (micro)glial cells and the effect of macrophages in vitro.
• Generating bone marrow chimeric mice (RAGE(-/-) to wild-type) to assess the role of bone marrow-derived cells.

Main Results:

• HMGB1 levels were elevated in serum of stroke patients and released from ischemic brain tissue in mice.
• Neutralizing HMGB1 or blocking its interaction with RAGE reduced ischemic brain damage.
• Genetic RAGE deficiency and soluble RAGE decreased infarct size.
• RAGE expression in (micro)glial cells mediated HMGB1 toxicity, enhanced by macrophages.
• RAGE deficiency in bone marrow-derived cells significantly reduced infarct size, indicating a role for immigrant macrophages.

Conclusions:

• The HMGB1-RAGE signaling pathway acts as a sensor for necrotic cell death in ischemic stroke.
• This pathway links necrosis to macrophage activation, contributing to inflammation and brain damage.
• Targeting the HMGB1-RAGE interaction offers a promising strategy for anti-inflammatory therapy in stroke.