High Mobility Group Box 1 Protein in Inflammation and Immune Response

High Mobility Group Box 1 protein (HMGB1) is a conserved nuclear factor that governs chromatin organisation and gene transcription. In response to stress or cell damage, HMGB1 undergoes post-translational modifications—such as acetylation, phosphorylation and redox changes—that drive its relocation to the cytoplasm and eventual release into the extracellular space. Once outside the cell, HMGB1 functions as a prototypical damage-associated molecular pattern and alarmin, engaging pattern recognition receptors including Toll-like receptor 4 and the receptor for advanced glycation end products to initiate cytokine production, leukocyte recruitment and tissue repair. Distinct oxidative forms of HMGB1 display selective receptor affinities, mediating activities from chemotaxis to inflammasome activation. Dysregulated HMGB1 signalling contributes to sepsis, autoimmune disorders, acute organ injury and chronic inflammation, while targeted inhibition of HMGB1 or its receptor interactions holds promise for therapeutic modulation of pathological immune responses.

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Technical terms

Damage-associated molecular pattern (DAMP): Endogenous molecules released by stressed or dying cells that activate innate immune receptors.

Alarmin: A DAMP that rapidly alerts and activates the immune system upon extracellular release.

Post-translational modification: Chemical modifications of proteins after synthesis that regulate their function, localisation and interactions.

Redox state: The oxidation status of specific amino acid residues within a protein, affecting its conformation and receptor binding.

Toll-like receptor 4 (TLR4): A pattern recognition receptor that recognises HMGB1 and other ligands to initiate proinflammatory signalling.

Receptor for advanced glycation end products (RAGE): A multiligand receptor involved in HMGB1-mediated endocytosis and amplification of inflammatory responses.

References

1. Targeting Inflammation Driven by HMGB1. Frontiers in Immunology (2020).
2. The mechanism of HMGB1 secretion and release. Experimental & Molecular Medicine (2022).
3. High‐mobility group box 1 protein orchestrates responses to tissue damage via inflammation, innate and adaptive immunity, and tissue repair. Immunological Reviews (2017).
4. Involvement of Toll-like Receptors 2 and 4 in Cellular Activation by High Mobility Group Box 1 Protein*. Journal of Biological Chemistry (2003).
5. High Mobility Group Box Protein 1 (HMGB1): The Prototypical Endogenous Danger Molecule. Molecular Medicine (2015).
6. The Role of HMGB1 in the Pathogenesis of Inflammatory and Autoimmune Diseases. Molecular Medicine (2014).
7. Oxidative stress-mediated HMGB1 biology. Frontiers in Physiology (2015).
8. HMGB1 promotes the activation of NLRP3 and caspase-8 inflammasomes via NF-κB pathway in acute glaucoma. Journal of Neuroinflammation (2015).
9. Extracellular HMGB1: a therapeutic target in severe pulmonary inflammation including COVID-19?. Molecular Medicine (2020).