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| Symbol | HMGB1 |
| Full Name |
High Mobility Group Box 1 |
| Chromosome |
13q12.3 |
| NCBI Gene |
3146 |
| Ensembl |
ENSG00000189403 |
| OMIM |
163905 |
| UniProt |
P09429 |
| Diseases |
[Alzheimer's Disease](/diseases/alzheimers), [Parkinson's Disease](/diseases/parkinsons-disease), [ALS](/diseases/als), Stroke, Traumatic Brain Injury |
| Expression |
Ubiquitous; enriched in [neurons](/entities/neurons), microglia, [astrocytes](/entities/astrocytes) |
DAMP (danger signal)
[TLR4](/entities/tlr4)/RAGE ligand
Nuclear DNA-binding protein
Redox-sensitive alarmin |
HMGB1 (High Mobility Group Box 1) is a gene on chromosome 13q12.3 encoding a highly conserved, ubiquitously expressed nuclear protein that functions both as a chromatin architectural factor and as an extracellular danger-associated molecular pattern (DAMP). In the nucleus, HMGB1 bends DNA and facilitates transcription factor binding. When released from damaged or dying neurons, HMGB1 acts as a potent alarmin that activates microglia and astrocytes through TLR4 and RAGE receptors, driving neuroinflammation in Alzheimer's disease, Parkinson's disease, ALS, and acute brain injuries.
Key takeaway: HMGB1 is a dual-function protein — chromatin regulator inside the nucleus, potent inflammatory mediator when released extracellularly. Its role as a DAMP makes it a central amplifier of neuroinflammation across neurodegenerative diseases.
¶ Gene Structure and Expression
HMGB1 spans approximately 7.5 kb on chromosome 13q12.3, comprising 5 exons. The gene is one of four HMGB family members (HMGB1-4), with HMGB1 being the most abundant and broadly expressed. The gene encodes a 215-amino acid protein with two DNA-binding HMG box domains (A-box and B-box) and an acidic C-terminal tail.
HMGB1 is expressed ubiquitously but shows enrichment in:
- Neurons: High nuclear expression in cortical, hippocampal, and cerebellar neurons
- Microglia: Expression increases dramatically upon activation; microglia are the primary source of extracellular HMGB1 in the CNS
- Astrocytes: Moderate expression, with active secretion during reactive astrogliosis
- Oligodendrocytes: Low basal expression
Expression data is available from the Allen Human Brain Atlas.
HMGB1 expression is regulated by:
- NF-κB: Inflammatory activation increases HMGB1 transcription
- p53: DNA damage response upregulates HMGB1
- Interferon regulatory factors: IRF1 and IRF3 regulate HMGB1 in innate immune responses
- Epigenetic control: Promoter methylation and histone acetylation modulate tissue-specific expression levels
Inside the nucleus, HMGB1 functions as a chromatin architectural protein:
- DNA bending: HMGB1 binds the minor groove of DNA and induces sharp bends, facilitating nucleosome remodeling and transcription factor access
- Transcription regulation: Enhances binding of p53, steroid hormone receptors, and NF-κB to their target sequences
- DNA repair: HMGB1 participates in base excision repair, nucleotide excision repair, and mismatch repair by facilitating access of repair enzymes
- V(D)J recombination: Required for proper immunoglobulin gene rearrangement
- Telomere maintenance: HMGB1 associates with telomeric DNA and regulates telomere length
When released extracellularly — passively from necrotic cells or actively secreted by activated immune cells — HMGB1 becomes a potent inflammatory mediator:
- RAGE signaling: HMGB1 binds the Receptor for Advanced Glycation End Products, activating NF-κB, MAPK cascades, and pro-inflammatory gene expression
- TLR4 activation: Disulfide-HMGB1 signals through TLR4/MD-2 complex, activating MyD88-dependent and TRIF-dependent pathways
- TLR2 engagement: HMGB1-nucleosome complexes activate TLR2 signaling
- CXCL12 partnership: HMGB1 forms a heterocomplex with the chemokine CXCL12 that signals through CXCR4 to recruit immune cells
- NLRP3 inflammasome activation: Extracellular HMGB1 primes and activates the NLRP3 inflammasome, leading to IL-1β and IL-18 release
HMGB1 activity is critically regulated by its redox state:
- All-thiol HMGB1 (C23, C45, C106 all reduced): Chemoattractant, promotes cell migration via CXCR4
- Disulfide HMGB1 (C23-C45 disulfide bond, C106 reduced): Pro-inflammatory cytokine inducer via TLR4
- Sulfonyl HMGB1 (C106 oxidized to sulfonic acid): Immunologically inactive, promotes resolution of inflammation
This redox switch makes HMGB1 a sensor of the tissue oxidative environment, directly coupling oxidative stress to inflammation.
HMGB1 plays multiple roles in AD pathogenesis:
- Amyloid amplification: Extracellular HMGB1 binds amyloid-β oligomers and fibrils, forming HMGB1-Aβ complexes that activate microglia more potently than Aβ alone
- Neuroinflammation: HMGB1 released from degenerating neurons activates microglial TLR4 and RAGE, sustaining chronic inflammation around amyloid plaques
- Tau pathology: HMGB1 promotes tau phosphorylation through RAGE-mediated GSK3β activation
- Blood-brain barrier disruption: HMGB1 increases BBB permeability through endothelial RAGE signaling
- CSF biomarker: Elevated HMGB1 levels in CSF correlate with disease severity and inflammatory markers
Postmortem studies show increased HMGB1 cytoplasmic translocation and extracellular release in AD hippocampus and cortex compared to age-matched controls.
In PD:
- HMGB1 is released from degenerating dopaminergic neurons in the substantia nigra
- Activates microglial TLR4 signaling, sustaining dopaminergic neurotoxicity
- α-Synuclein aggregates trigger HMGB1 release from neurons
- Anti-HMGB1 antibodies are neuroprotective in MPTP and 6-OHDA PD models
- HMGB1 levels are elevated in PD patient serum and CSF
In amyotrophic lateral sclerosis:
- HMGB1 is released from degenerating motor neurons
- Activates spinal cord microglia and astrocytes through TLR4 and RAGE
- Plasma HMGB1 levels correlate with disease progression rate
- TDP-43 aggregation promotes HMGB1 nuclear-to-cytoplasmic translocation
¶ Stroke and Traumatic Brain Injury
- Massive HMGB1 release occurs within hours of ischemic injury
- HMGB1 is one of the earliest DAMPs released after neuronal death
- Anti-HMGB1 strategies reduce infarct volume in preclinical stroke models
¶ Developmental and Aging Patterns
| Context |
HMGB1 Level |
Significance |
| Embryonic brain |
Very high (nuclear) |
Chromatin remodeling, neurogenesis |
| Adult brain |
Moderate (nuclear) |
Transcription regulation |
| Aging brain |
Increased cytoplasmic |
Cellular stress, senescence |
| AD brain |
High extracellular |
Neuroinflammation amplification |
| Post-injury |
Massive release |
DAMP signaling, sterile inflammation |
HMGB1 undergoes a characteristic nuclear-to-cytoplasmic translocation during neurodegeneration:
- Nuclear HMGB1 is hyperacetylated by stress-activated acetyltransferases
- Acetylation exposes nuclear export signals, driving cytoplasmic accumulation
- Cytoplasmic HMGB1 is actively secreted via lysosomal exocytosis or passively released during necrosis
- Extracellular HMGB1 amplifies inflammation through paracrine and autocrine loops
- Anti-HMGB1 monoclonal antibodies: Neutralizing antibodies reduce neuroinflammation in AD, PD, and stroke models
- BoxA (HMGB1 antagonist): The A-box domain of HMGB1 acts as a competitive antagonist, blocking HMGB1-receptor interactions
- Glycyrrhizin: Natural compound from licorice root that directly binds HMGB1 and inhibits its extracellular activity; neuroprotective in multiple preclinical models
- Ethyl pyruvate: Inhibits HMGB1 secretion by activated macrophages/microglia
- RAGE inhibitors: FPS-ZM1 and other small molecule RAGE antagonists block HMGB1-RAGE signaling
- TLR4 antagonists: TAK-242 (resatorvid) blocks HMGB1-TLR4 signaling
- HMGB1 is a validated therapeutic target in multiple inflammatory conditions
- The redox-dependent activity provides opportunities for selective targeting
- Combination with anti-amyloid or anti-tau therapies may address both pathology triggers and inflammatory amplification