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HMGB1: A multifunctional alarmin driving autoimmune and inflammatory disease

Abstract

HMGB1 is a non-histone nuclear protein that can serve as an alarmin to drive the pathogenesis of inflammatory and autoimmune disease. Although primarily located in the cell nucleus, HMGB1 can translocate to the cytoplasm, as well as the extracellular space, during cell activation and cell death; during activation, HMGB1 can undergo post-translational modifications. The activity of HMGB1 varies with the redox states of the cysteine residues, which are required for binding to TLR4. In addition to stimulating cells directly, HMGB1 can form immunostimulatory complexes with cytokines and other endogenous and exogenous factors. In the synovia of patients with rheumatoid arthritis, as well as animal models of this disease, extranuclear expression of HMGB1 is increased and blockade of HMGB1 expression attenuates disease in animal models. In systemic lupus erythematosus, HMGB1 can be a component of immune complexes containing anti-DNA because of its interaction with DNA. In myositis, expression of HMGB1 is enhanced in inflamed muscle and can perturb muscle function. Together, these findings indicate that HMGB1 might be an important mediator and biomarker in rheumatic diseases as well as a target of new therapy.

Key Points

  • HMGB1 is a non-histone protein that has key roles inside and outside the cell; inside the cell, HMGB1 can bind to DNA as an architectural element

  • During activation and cell death, HMGB1 can translocate from the nucleus to the extracellular space; extracellular HMGB1 serves as an alarmin to mediate inflammation

  • Depending on its redox state, HMGB1 can stimulate cells through a variety of receptors, including Toll-like receptors, acting alone or in complex with other immune stimulants

  • Extracellular HMGB1 levels are elevated in patients with inflammatory and autoimmune disease

  • Studies in animals using HMGB1 antagonists support the notion that they should be a target of therapy in various autoimmune and inflammatory diseases

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Figure 1: The structure and function of HMGB1.
Figure 2: The extracellular release of HMGB1.
Figure 3: Signaling by HMGB1.
Figure 4: HMGB1 expression in mouse collagen-induced arthritis.

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Acknowledgements

This work was supported by grants from Swedish Research Council, Karolinska Institutet, Karolinska University Hospital, the Swedish Rheumatism Association, a VA Merit Review Grant and NIH AI-056363.

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Correspondence to David S. Pisetsky.

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Supplementary information

Supplementary Table 1

Biological activities of extracellular HMGB1 (DOC 61 kb)

Supplementary Table 2

Experimental disease models responding to therapy targeting HMGB1 (DOC 60 kb)

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Harris, H., Andersson, U. & Pisetsky, D. HMGB1: A multifunctional alarmin driving autoimmune and inflammatory disease. Nat Rev Rheumatol 8, 195–202 (2012). https://doi.org/10.1038/nrrheum.2011.222

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