HMGB1 and RAGE in Inflammation and Cancer
Abstract
The immune system has evolved to respond not only to pathogens, but also to signals released from dying cells. Cell death through necrosis induces inflammation, whereas apoptotic cell death provides an important signal for tolerance induction. High mobility group box 1 (HMGB1) is a DNA-binding nuclear protein, released actively following cytokine stimulation as well as passively during cell death; it is the prototypic damage-associated molecular pattern (DAMP) molecule and has been implicated in several inflammatory disorders. HMGB1 can associate with other molecules, including TLR ligands and cytokines, and activates cells through the differential engagement of multiple surface receptors including TLR2, TLR4, and RAGE. RAGE is a multiligand receptor that binds structurally diverse molecules, including not only HMGB1, but also S100 family members and amyloid-β. RAGE activation has been implicated in sterile inflammation as well as in cancer, diabetes, and Alzheimer's disease. While HMGB1 through interactions with TLRs may also be important, this review focuses on the role of the HMGB1-RAGE axis in inflammation and cancer.
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HMGB1 mediates pro-inflammatory effects by binding TLR2, TLR4, and RAGE; TLR4 is the sole HMGB1 receptor relevant to perceive cell death as immunogenic.
“Once secreted, the non-histone chromatin-binding protein HMGB1 mediates potent pro-inflammatory effects by binding to TLR2, TLR4, and advanced glycosylation end product-specific receptor (AGER; best known as RAGE) [912], although TLR4 seems to be the sole HMGB1 receptor relevant to perceive cell death as immunogenic [870 913–915].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [912]
RAGE is a transmembrane receptor expressed by immune cells, endothelial cells, cardiomyocytes and neurons.
“RAGe is a transmembrane receptor that is expressed by immune cells, endothelial cells, cardiomyocytes and neurons89–91.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [90]
RAGE contains no obvious signalling domains.
“The protein contains no obvious signalling domains90, although extracellular signal-regulated kinase (eRK) was shown to directly interact with the cytoplasmic tail of RAGe97.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [90]
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- Authors
- Sims, G. P., Rowe, D. C., Rietdijk, S. T., Herbst, R., & Coyle, A. J.
- Affiliations
- Department of Respiratory, Inflammation and Autoimmune Disease, MedImmune, One Medimmune Way, Gaithersburg, Maryland 20878;
- Amsterdam UMC Location University of Amsterdam (NL)
- Venue
- Annual Review of Immunology
- Publisher
- Annual Reviews
- Published
- 2010-03-01
- Volume
- 28
- Issue
- 1
- Pages
- 367-388
- ISSN
- 0732-0582 (ISSN-L)
- 1545-3278
- OpenAlex
- W2106949373
- Cited by
- 1,436
- References
- 15
- Citations by year
- 2026: 57 · 2025: 59 · 2024: 78 · 2023: 84 · 2022: 84 · 2021: 107 · 2020: 83 · 2019: 91 · 2018: 86 · 2017: 89 · 2016: 82 · 2015: 94 · 2014: 117 · 2013: 108 · 2012: 107
- FWCI
- 10.58
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annual Review of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › S100 Proteins and Annexins
- Keywords
- HMGB1, receptor for advanced glycation end products, damage-associated molecular patterns, sterile inflammation, cancer, necrosis, apoptosis, TLR2, TLR4, S-100 protein, amyloid-beta, tumor microenvironment
- MeSH terms
- Receptor for Advanced Glycation End Products, Animals, Humans, Inflammation, Ligands, Neoplasms, Receptors, Immunologic, Signal Transduction, HMGB1 Protein
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