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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.
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“Moreover, the expression of HMGB1, an alarmin that conveys injury signals to surrounding cells, was higher in the AD-up-regulated subpopulations than the AD-down-regulated subpopulation (SI Appendix, Fig. S5D) (20).”
From Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimer’s disease (2020) · cites this paper as [20]
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“TFAM is a DNA-binding protein belonging to the same family as high mobility group box 1 protein and is a very important alarmin involved in inflammation and autoimmune disorders209.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [209]
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Metadata
- Authors
- Harris, H. E., Andersson, U., & Pisetsky, D. S.
- Affiliations
- Karolinska Institutet (SE)
- Karolinska University Hospital (SE)
- Durham VA Medical Center (US)
- Corresponding author
- Pisetsky, David S.
- Venue
- Nature Reviews Rheumatology
- Published
- 2012-01-31
- Volume
- 8
- Issue
- 4
- Pages
- 195-202
- ISSN
- 1759-4790 (ISSN-L)
- 1759-4804
- OpenAlex
- W1972204333
- Cited by
- 689
- References
- 93
- Citations by year
- 2026: 20 · 2025: 31 · 2024: 32 · 2023: 34 · 2022: 54 · 2021: 61 · 2020: 50 · 2019: 59 · 2018: 65 · 2017: 57 · 2016: 53 · 2015: 52 · 2014: 55 · 2013: 49 · 2012: 16
- FWCI
- 6.55
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Reviews Rheumatology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Vetenskapsrådet
- Reumatikerförbundet
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (AI-056363, U19AI056363)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Keywords
- HMGB1, alarmins, non-histone nuclear proteins, rheumatoid arthritis, systemic lupus erythematosus, myositis, inflammation, autoimmune disease, TLR4, post-translational modification, cysteine redox state, extracellular HMGB1, immune complexes, anti-DNA antibodies, synovium, biomarkers, therapeutic target
- MeSH terms
- Animals, Autoimmune Diseases, DNA-Binding Proteins, Humans, Inflammation, Rheumatic Diseases, Signal Transduction, HMGB1 Protein
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