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Updated: Apr 18, 2026

Morphological and Compositional Analysis of Neutrophil Extracellular Traps Induced by Microbial and Chemical Stimuli
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The HMGB1/RAGE axis triggers neutrophil-mediated injury amplification following necrosis

Peter Huebener, Jean-Philippe Pradere, Celine Hernandez

    The Journal of Clinical Investigation
    |January 7, 2015
    PubMed

    Insights

    High-mobility group box 1 (HMGB1) released by epithelial cells drives sterile inflammation and injury amplification in necrosis. Targeting HMGB1 offers a potential therapeutic strategy for necrosis-related conditions.

    Area of Science:

    • Immunology
    • Cell Biology
    • Pathology

    Background:

    • Sterile inflammation mechanisms are poorly understood compared to microbially triggered inflammation.
    • Damage-associated molecular patterns (DAMPs) are implicated in sterile inflammation, but the role of high-mobility group box 1 (HMGB1) remains debated due to knockout mouse lethality.

    Purpose of the Study:

    • To elucidate the specific role of HMGB1 in sterile inflammation and disease processes in vivo.
    • To investigate the cellular source and downstream effects of HMGB1 in different types of cell death and inflammatory conditions.

    Main Methods:

    • Conditional HMGB1 ablation strategies in mice.
    • Assessment of sterile inflammation following injury, focusing on necrosis and apoptosis.
    • Evaluation of neutrophil and macrophage recruitment.
    • Analysis of disease models including acetaminophen intoxication, TNF/FAS-mediated apoptosis, and LPS-induced shock.

    Main Results:

    • Epithelial HMGB1, not bone marrow-derived HMGB1, is essential for sterile inflammation post-injury.
    • HMGB1/RAGE signaling promotes neutrophil recruitment to necrotic cells, amplifying injury via neutrophil elastase.
    • Hepatocyte-specific HMGB1 ablation conferred 100% survival in lethal acetaminophen intoxication.
    • HMGB1 ablation did not affect inflammation or mortality in TNF/FAS-mediated apoptosis or LPS-induced shock.

    Conclusions:

    • HMGB1 is a critical DAMP that selectively initiates a neutrophil-mediated injury amplification loop in necrosis.
    • HMGB1 emerges as a targetable mediator in sterile inflammation, particularly in necrotic injury settings.
    • HMGB1's role in apoptosis and LPS-induced shock appears limited, contrasting its critical function in necrosis.

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